Bookshelf NBK248069

National Clinical Guideline Centre
Osteoarthritis
Care and management in adults
Clinical guideline CG177

Methods, evidence and recommendations
February 2014
Commissioned by the National Institute for Health and Care

Excellence
Osteoarthritis
Contents
Disclaimer
Healthcare professionals are expected to take NICE clinical guidelines fully into account when
exercising their clinical judgement. However, the guidance does not override the responsibility of
healthcare professionals to make decisions appropriate to the circumstances of each patient, in
consultation with the patient and/or their guardian or carer.
Copyright
National Clinical Guideline Centre, 2014
Funding
National Institute for Health and Care Excellence

Osteoarthritis
Contents
Contents
Guideline development group members ......................................................................................11
Acknowledgements ....................................................................................................................13
1 Introduction ........................................................................................................................14
1.1 What is osteoarthritis?........................................................................................................ 14
1.2 Risk factors for osteoarthritis.............................................................................................. 15
1.3 The epidemiology of osteoarthritis pain and structural pathology .................................... 15
1.4 Prognosis and Outcome ...................................................................................................... 16
1.5 The impact on the individual .............................................................................................. 17
1.6 The impact on society ......................................................................................................... 18
1.7 Features of the evidence base for osteoarthritis ................................................................ 18
2 Development of the guideline ..............................................................................................20
2.1 What is a NICE clinical guideline? ....................................................................................... 20
2.2 Who developed this guideline? .......................................................................................... 20
2.3 What this guideline covers .................................................................................................. 21
2.4 What this guideline does not cover .................................................................................... 21
2.5 Relationships between the guideline and other NICE guidance ......................................... 21
3 Methods ..............................................................................................................................23
3.1 Developing the review questions and outcomes................................................................ 23
3.2 Searching for evidence ........................................................................................................ 25
3.2.1 Clinical literature search......................................................................................... 25
3.2.2 Health economic literature search ......................................................................... 26
3.3 Evidence of effectiveness.................................................................................................... 26
3.3.1 Inclusion/exclusion................................................................................................. 26
3.3.2 Methods of combining clinical studies ................................................................... 27
3.3.3 Appraising the quality of evidence by outcomes ................................................... 28
3.3.4 Grading the quality of clinical evidence ................................................................. 29
3.3.5 Study limitations..................................................................................................... 30
3.4 Evidence of cost-effectiveness ............................................................................................ 33
3.4.1 Literature review .................................................................................................... 33
3.4.3 Cost-effectiveness criteria...................................................................................... 35
3.4.4 In the absence of economic evidence .................................................................... 36
3.5 Developing recommendations ............................................................................................ 36
3.5.1 Research recommendations .................................................................................. 36
3.5.4 Disclaimer ............................................................................................................... 37
3.5.5 Funding ................................................................................................................... 37
4 Guideline summary ..............................................................................................................38

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4.1 Algorithms ........................................................................................................................... 38

4.1.1 Holistic assessment ................................................................................................ 38
4.1.2 Targeting treatment ............................................................................................... 39
4.2 Key priorities for implementation....................................................................................... 40
4.3 Full list of recommendations .............................................................................................. 41
4.4 Key research recommendations ......................................................................................... 45
5 Diagnosis .............................................................................................................................46
5.1 Introduction ........................................................................................................................ 46
5.1.1 In a person with suspected clinical OA (including knee pain) when would the
addition of imaging be indicated to confirm additional or alternative
diagnoses (particularly to identify red flags) such as: ............................................ 47
5.1.2 Clinical evidence ..................................................................................................... 49
5.1.3 Economic evidence................................................................................................. 67
5.1.4 Evidence statements .............................................................................................. 67
5.1.5 Recommendations and link to evidence ................................................................ 69
6 Holistic approach to osteoarthritis assessment and management .........................................72
6.1 Principles of good osteoarthritis care ................................................................................. 72
6.1.1 Recommendations ................................................................................................. 72
6.2 Patient experience and perceptions ................................................................................... 72
6.2.1 Clinical introduction ............................................................................................... 72
6.2.2 Methodological introduction ................................................................................. 73
6.2.4 From evidence to recommendations ..................................................................... 77
7 Education and self-management ..........................................................................................81
7.1 Patient information ............................................................................................................. 81
7.1.1 Clinical Introduction ............................................................................................... 81
7.1.5 Recommendation ................................................................................................... 92
7.2 Decision aids ....................................................................................................................... 92
7.2.1 Introduction ........................................................................................................... 92
7.2.2 What is the clinical and cost-effectiveness of decision aids for the
management of OA? .............................................................................................. 92
7.2.3 Clinical evidence ..................................................................................................... 93
7.2.4 Economic evidence................................................................................................. 96
7.2.6 Recommendations and link to evidence ................................................................ 96
7.3 Patient self-management interventions ............................................................................. 98

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7.3.2 Evidence base ......................................................................................................... 98
7.3.4 Recommendations ................................................................................................. 99
7.4 Rest, relaxation and pacing ................................................................................................. 99
7.4.4 From evidence to recommendations ................................................................... 100
7.5 Thermotherapy ................................................................................................................. 100
7.5.1 Clinical introduction ............................................................................................. 100
7.5.2 Methodological introduction ............................................................................... 100
7.5.3 Evidence statements ............................................................................................ 100
7.5.5 Recommendations ............................................................................................... 103
8 Non-pharmacological management of osteoarthritis .......................................................... 104
8.1 Exercise and manual therapy ............................................................................................ 104
8.1.2 Methodological introduction: exercise ................................................................ 104
8.1.3 Methodological introduction: manual therapy .................................................... 105
8.1.4 Evidence statements: land-based exercise .......................................................... 106
8.1.5 Evidence statements: comparing different land-based exercise regimens ......... 117
8.1.6 Evidence statements: hydrotherapy .................................................................... 122
8.1.7 Evidence statements: exercise vs manual therapy .............................................. 126
8.1.8 Evidence statements: manual therapy ................................................................ 129
8.1.9 Health economic evidence overview ................................................................... 138
8.1.10 Health economic evidence statements ................................................................ 140
8.2 Weight loss ........................................................................................................................ 145
8.3 Electrotherapy................................................................................................................... 149

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8.3.3 Evidence statements: ultrasound ........................................................................ 151

8.3.4 Evidence statements: laser .................................................................................. 152
8.3.5 Evidence statements: TENS .................................................................................. 154
8.3.6 Evidence statements: PEMF ................................................................................. 161
8.4 Nutraceuticals ................................................................................................................... 164
8.4.1 Introduction ......................................................................................................... 164
8.4.2 What is the clinical and cost effectiveness of glucosamine and chondroitin
alone or in compound form versus placebo or other treatments in the
management of osteoarthritis? ........................................................................... 165
8.4.3 Clinical evidence ................................................................................................... 165
8.4.4 Economic evidence............................................................................................... 191
8.4.6 Recommendations and link to evidence .............................................................. 201
8.5 Acupuncture ...................................................................................................................... 206
8.5.1 Introduction ......................................................................................................... 206
8.5.2 What is the clinical and cost-effectiveness of acupuncture versus sham
treatment ( sham control) and other interventions in the management of
osteoarthritis? ...................................................................................................... 206
8.6 Aids and devices ................................................................................................................ 231
8.6.3 Evidence statements: footwear, bracing and walking aids .................................. 232
8.6.4 Evidence statements: assistive devices ................................................................ 246
8.7 Invasive treatments for knee osteoarthritis ..................................................................... 250
9 Pharmacological management of osteoarthritis .................................................................. 259
9.1 Introduction ...................................................................................................................... 259
9.1.1 Methodological introduction: paracetamol versus NSAIDs including COX-2

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inhibitors .............................................................................................................. 259

9.1.2 Methodological introduction: paracetamol versus opioids, and paracetamol-
opioid combinations............................................................................................. 260
9.1.3 Methodological introduction: opioids.................................................................. 261
9.1.4 Methodological introduction: paracetamol vs placebo ....................................... 262
9.1.5 Methodological introduction: tricyclics, SSRIs and SNRIs .................................... 262
9.1.6 Evidence statements: paracetamol versus NSAIDs including COX-2 inhibitors ... 263
9.1.7 Evidence statements: paracetamol versus opioids, and paracetamol-opioid
combinations ........................................................................................................ 268
9.1.8 Evidence statements: opioids .............................................................................. 272
9.1.9 Evidence statements: paracetamol versus placebo ............................................. 280
9.1.10 Evidence statements: tricyclics, SSRIs and SNRIs ................................................. 284
9.2 Topical treatments ............................................................................................................ 286
9.2.3 Evidence Statements: topical NSAIDs .................................................................. 288
9.2.4 Evidence statements: topical capsaicin versus placebo ...................................... 293
9.2.5 Evidence statements: topical rubefacients .......................................................... 296
9.2.6 Health economic evidence ................................................................................... 300
9.2.7 Health economic evidence statements ................................................................ 301
9.3 NSAIDs and highly selective COX-2 inhibitors ................................................................... 304
9.3.3 Evidence statements: COX-2 inhibitors vs placebo and NSAIDs .......................... 305
9.3.4 Evidence statements: co-prescription of a proton pump inhibitor ..................... 314
9.3.6 Health economic modelling (CG59) ..................................................................... 317
10 Intra-articular Injections .................................................................................................... 322
10.1 Introduction ...................................................................................................................... 322
10.1.1 Methodological introduction: corticosteroids ..................................................... 322
10.1.2 Evidence statements: Intraarticular (IA) corticosteroids vs placebo ................... 323

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10.2 Intra-articular injections of hyaluronic acid/ hyaluronans in the management of OA in

the knee, hand, ankle, big toe and hip.............................................................................. 327
10.2.1 What is the clinical and cost effectiveness of intra-articular injections of
hyaluronic acid/ hyaluronans in the management of OA in the knee, hand,
ankle, big toe and hip? ......................................................................................... 327
11 Referral for specialist services ............................................................................................ 407
11.1 Referral criteria for surgery............................................................................................... 407
11.1.2 Methodological introduction: indications for joint replacement ........................ 407
11.1.3 Methodological introduction: predictors of benefit and harm............................ 408
11.1.4 Evidence statements: indications for joint replacement ..................................... 408
11.1.5 Evidence statements: predictors of benefit and harm ........................................ 419
12 Consideration of timing for surgery .................................................................................... 433
12.1 Introduction ...................................................................................................................... 433
12.1.1 What information should people with OA receive to inform consideration of
the appropriate timing of referral for surgery as part of their OA
management? ...................................................................................................... 433
13 Patient follow-up ............................................................................................................... 442
13.1 Introduction ...................................................................................................................... 442
13.1.1 What is the clinical and cost effectiveness of regular follow-up or review in
reinforcing core treatments (information, education, exercise, weight
reduction) care in the management of OA? ........................................................ 442
13.2 Which patients with OA will benefit the most from reinforcement of core treatment
as part of regular follow-up/review? ................................................................................ 460
14 Reference list..................................................................................................................... 461

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15 Glossary ............................................................................................................................ 498

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Guideline development group members

2008
Name Role
Professor Philip Conaghan Chair of the GDG
Dr John Dickson Clinical Advisor to the GDG, and Clinical Lead for Musculoskeletal Services
Dr Fraser Birrell Consultant Rheumatologist
Professor Paul Dieppe Professor of Health Services Research
Professor Michael Doherty Consultant Rheumatologist
Professor Krysia Dziedzic Physiotherapist
Dr Michael Burke General Practitioner
Professor Roger Francis Professor of Geriatric Medicine
Mrs Christine Kell Patient Member
Mrs Jo Cumming Patient Member
Dr Richard Frearson Geriatrician
Dr Alex MacGregor Professor of Chronic Diseases Epidemiology
Mrs Susan Oliver Nurse Consultant in Rheumatology
Ms Carolyn Naisby Consultant Physiotherapist
Dr Martin Underwood Vice-dean, Warwick Medical School
Co-opted experts
Name Role
Dr Mark Porcheret General Practitioner
Dr Marta Buszewicz Senior Lecturer in Community Based Teaching & Research
Dr Alison Carr Lecturer in Musculoskeletal Epidemiology
Mr Mark Emerton Consultant Orthopaedic Surgeon,
Professor Edzard Erns Laing Professor of Complementary Medicine
Dr Alison Hammond ARC Senior Lecturer
Dr Mike Hurley Reader in Physiotherapy & ARC Research Fellow
Professor Andrew McCaskie Professor of Orthopaedics
Dr Tony Redmond ARC Lecturer in Podiatric Rheumatology
Dr Adrian White Clinical Research Fellow
Ms Rahana Mohammed of
Arthritis Care attended one
meeting as a deputy for Jo
Cumming.
2014
Name Role
Update 2014
Professor Philip Conaghan Chair of the GDG

Dr Fraser Birrell Consultant Rheumatologist
Dr Mark Porcheret Arthritis Research UK Senior Lecturer in General Practice
Professor Michael Doherty Head of Academic Rheumatology
Professor Krysia Dziedzic Arthritis Research UK Professor of Musculoskeletal Therapies

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Name Role
Dr Ian Bernstein Musculoskeletal Physician
Dr Elspeth Wise General Practitioner
Mr Tony Whiting Patient Member
Mrs Jo Cumming Patient Member
Dr Richard Frearson Consultant Physician/Geriatrician
Dr Erika Baker Senior Pharmacist
Professor Peter Kay Consultant Lower Limb Arthroplasty Surgeon and Associate Medical Director
Dr Robert Middleton Consultant Orthopaedic Surgeon
Dr Brian Lucas Lead Nurse
Professor Weiya Zhang Associate Professor and Reader in Musculoskeletal Epidemiology
Update 2014
Co-opted experts
Name Role
Dr Jonathan Spratt Radiologist
Dr Jens Foell GP and acupuncturist
Ms Jill Halstead Podiatrist
Ms Kirsty Bancroft Occupational Therapist
Professor Andrew Price Professor of Orthopaedic Surgery
NCGC
Name Role
Susan Latchem Guideline Lead
Paul Miller Senior information scientist
Vanessa Nunes Senior Research Fellow and Project Manager
Dr Emmert Roberts Research Fellow
Margaret Constanti Health Economist

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Acknowledgements
Acknowledgements
2008
The GDG are grateful to Bernard Higgins, Jane Ingham, Ian Lockhart, Jill Parnham, Nicole Stack, Susan
Tann and Claire Turner of the NCC-CC for their support throughout the development of the guideline.
The GDG would especially like to record their gratitude for the great amount of work voluntarily
given to the refinement of the economic model of non-steroidal anti-inflammatory drugs by Dr
Joanne Lord of the National Institute for Health and Care Excellence. The GDG would also like to
thank the following individuals for giving their time to advise us on the design and interpretation of
the economic model:
• Dr Phil Alderson, National Institute for Health and Care Excellence
• Mr Garry Barton, School of Economics, University of Nottingham
• Professor Chris Hawkey, Institute of Clinical Research, University of Nottingham
• Professor Tom MacDonald, Hypertension Research Centre & Medicines Monitoring Unit,
University of Dundee
• Dr Jayne Spink, National Institute for Health and Care Excellence
• Dr Rafe Suvarna, Medicines and Healthcare Regulatory Agency
• Professor Richard Thomson, Professor of Epidemiology and Public Health, University of

Newcastle upon Tyne
• Dr Weiya Zhang, Associate Professor, Centre for Population Sciences, University of

Nottingham
Update 2014
2014
The GDG are grateful to Hati Zorba, Tamara Diaz, Katie Jones, Serena Carville, David Wonderling,
Professor Nigel Arden, Professor Martin Underwood, Professor Mark Baker, Ben Doak and Dr Martin
Allaby, for their support throughout the development of the guideline.

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Osteoarthritis
Introduction
1 Introduction
1.1 What is osteoarthritis?
Osteoarthritis refers to a clinical syndrome of joint pain accompanied by varying degrees of
functional limitation and reduced quality of life. It is the most common form of arthritis, and one of
the leading causes of pain and disability worldwide. The most commonly affected peripheral joints
are the knees, hips and small hand joints. Although pain, reduced function and effects on a person’s
ability to carry out their day-to-day activities can be important consequences of osteoarthritis, pain
in itself is of course a complex biopsychosocial issue, related in part to person expectations and self-
efficacy, and associated with changes in mood, sleep and coping abilities. There is often a poor link
between changes on an X-ray and symptoms: minimal changes can be associated with a lot of pain
and modest structural changes to joints oftencan occur without with minimal accompanying
symptoms. Contrary to popular belief, osteoarthritis is not caused by ageing and does not necessarily
deteriorate. There are a number of management and treatment options (both pharmacological and
non-pharmacological), which this guideline addresses and which offer effective interventions for
control of symptoms and improving function.
Osteoarthritis is characterised pathologically by localised loss of cartilage, remodelling of adjacent

bone and associated inflammation. A variety of traumas may trigger the need for a joint to repair
itself. Osteoarthritis includes a slow but efficient repair process that often compensates for the initial
trauma, resulting in a structurally altered but symptom-free joint. In some people, because of either
overwhelming trauma or compromised repair, the process cannot compensate, resulting in eventual
Update 2014
presentation with symptomatic osteoarthritis; this might be thought of as ‘joint failure’. This in part
explains the extreme variability in clinical presentation and outcome that can be observed between
people, and also at different joints in the same person.
There are limitations to the published evidence on treating osteoarthritis. Most studies have focused
on knee osteoarthritis, and are often of short duration using single therapies. Although most trials
have looked at single joint involvement, in reality many people have pain in more than one joint,
which may alter the effectiveness of interventions.
This guideline update was originally intended to include recommendations based on a review of new
evidence about the use of paracetamol, etoricoxib and fixed-dose combinations of NSAIDs plus
gastroprotective agents in the management of osteoarthritis. Draft recommendations based on the
evidence reviews for these areas were presented in the consultation version of the guideline.
Stakeholder feedback at consultation indicated that the draft recommendations, particularly in
relation to paracetamol, would be of limited clinical application without a full review of evidence on
the pharmacological management of osteoarthritis. NICE was also aware of an ongoing review by the
MHRA of the safety of over-the-counter analgesics. Therefore NICE intends to commission a full
review of evidence on the pharmacological management of osteoarthritis, which will start once the
MHRA’s review is completed, to inform a further guideline update.
Until that update is published, the original recommendations (from 2008) on the pharmacological
management of osteoarthritis remain current advice. However, the GDG would like to draw attention
to the findings of the evidence review on the effectiveness of paracetamol that was presented in the
consultation version of the guideline. That review identified reduced effectiveness of paracetamol in
the management of osteoarthritis compared with what was previously thought. The GDG believes
that this information should be taken into account in routine prescribing practice until the intended
full review of evidence on the pharmacological management of osteoarthritis is published (see the
NICE website for further details).

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Introduction
1.2 Risk factors for osteoarthritis

Osteoarthritis is defined not as a disease or a single condition but as a “common complex disorder”
with multiple risk factors. These risk factors are broadly divisible into:
 genetic factors (heritability estimates for hand, knee and hip osteoarthritis are high at 40-60%,
though the responsible genes are largely unknown);
 constitutional factors (for example, ageing, female sex, obesity, high bone density); and
 more local, largely biomechanical risk factors (for example, joint injury, occupational/recreational
usage, reduced muscle strength, joint laxity, joint malalignment).
Importantly, many environmental/lifestyle risk factors are reversible (for example, obesity, muscle
weakness) or avoidable (e.g. occupational or recreational joint trauma) which has important
implications for secondary and primary prevention. However, the importance of individual risk
factors varies, and even differs, between joint sites. Also, risk factors for developing osteoarthritis
may differ from risk factors for progression and poor clinical outcome (for example, high bone
density is a risk factor for development, but low bone density is a risk factor for progression of knee
and hip osteoarthritis). This means that knowledge, including treatments, for osteoarthritis at one
joint site cannot necessarily be extrapolated to all joint sites.
1.3 The epidemiology of osteoarthritis pain and structural pathology

The exact incidence and prevalence of osteoarthritis is difficult to determine because the clinical
syndrome of osteoarthritis (joint pain and stiffness) does not always correspond with the structural
changes of osteoarthritis (usually defined as abnormal changes in the appearance of joints on
radiographs). This area is becoming more complex with sensitive imaging techniques such as
magnetic resonance imaging which demonstrate more frequent structural abnormalities than
detected by radiographs.
Osteoarthritis at individual joint sites (notably knee, hip and hand) demonstrates consistent age-
related increases in prevalence.13 However symptomatic osteoarthritis is not an inevitable
consequence of ageing. Although prevalence of osteoarthritis rises in frequency with age, it does
affect substantial numbers of people of working age. The number of people with osteoarthritis in
the UK is increasing as the population ages, and as the prevalence of risk factors such as obesity and
poor levels of physical fitness also continues to rise.
Joint pain
The cause of joint pain in osteoarthritis is not well understood. Estimates suggest that up to 8.5
million people in the UK are affected by joint pain that may be attributed to osteoarthritis.14
Population estimates of the prevalence of joint symptoms depend heavily on the specific definition
used, but there is general agreement that the occurrence of symptoms is more common than
radiographic osteoarthritis in any given joint among older people. This may be due to joint pain
Update 2014
arising from causes other than osteoarthritis (for example, bursitis, tendonitis), differing radiographic
protocols views of a joint, or the insensitivity of radiographs for detecting structural abnormalities
that are better seen with imaging modalities such as magnetic resonance imaging (MRI) 173.
In adults 45 years and over the most common site of peripheral joint pain lasting for more than one
week in the past month is in the knee (19%) and the highest prevalence of knee pain is amongst
women aged 75 and over (35%).466 Global disability is also high amongst those reporting isolated
knee pain. In adults aged 50 years and over 23% report severe pain and disability.220 One-month
period prevalence of hand pain ranges from 12% in adults 45 years and over466 to 30% in adults 50
years133 and over and is more common in females than males, increasing in prevalence in the oldest
age groups.133

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Introduction
Radiographic osteoarthritis
Although joint pain is more common than radiographic osteoarthritis, much radiographic
osteoarthritis occurs in the absence of symptoms. At least 4.4 million people in the UK have X-ray
evidence of moderate to severe osteoarthritis of their hands, over 0.5 million have moderate to
severe osteoarthritis of the knees and 210,000 have moderate to severe osteoarthritis of the
hips.13,15 The prevalence of radiographic osteoarthritis, like symptoms, is also dependent on the
particular images acquired and definitions used.131
The prevalence of radiographic osteoarthritis is higher in women than men, especially after age 50
and for hand and knee osteoarthritis. Radiographic osteoarthritis of the knee affects about 25% of
community populations of adults aged 50 years and over.348
Ethnic differences in radiographic osteoarthritis prevalence have been more difficult to distinguish,
especially in studied African-American groups, but recent reports349 comparing Chinese and US
populations have demonstrated much lower levels of hip osteoarthritis in the Chinese, although
levels of knee and hand osteoarthritis generally were similar despite varying patterns.
The relationship between symptomatic and radiographic osteoarthritis
Although symptoms and radiographic changes do not always overlap, radiographic osteoarthritis is
still more common in persons with a longer history and more persistent symptoms. There is a
consistent association at the knee, for example, between severity of pain, stiffness, and physical
function and the presence of radiographic osteoarthritis.130 Concordance between symptoms and
radiographic osteoarthritis seems greater with more advanced structural damage.349
Half of adults aged 50 years and over with radiographic osteoarthritis of the knee have symptoms.349
Of the 25% of older adults with significant knee joint pain, two-thirds have radiographic disease. The
prevalence of painful, disabling radiographic knee osteoarthritis in the UK populations over 55 has
been estimated at approximately 10%. The prevalence of symptomatic radiographic osteoarthritis is
higher in women than men, especially after age 50. Within the knee joint of symptomatic
individuals, the most common radiographic osteoarthritis pattern of involvement is combined
tibiofemoral and patellofemoral changes.131 Although there are few good studies, symptomatic
radiographic hand osteoarthritis has been reported in less than 3% of populations, while rates of
symptomatic radiographic hip osteoarthritis have varied from 5 to 9%.
Table 1: Prevalence of radiographic and symptomatic osteoarthritis in older adults

Radiographic osteoarthritis Symptomatic osteoarthritis
348
Knee 25% 13%
92,255
Hip 11% 5%
491
Hand 41% 3%
1.4 Prognosis and Outcome

A common misconception in the UK, within both the public and many health care professionals, is
that osteoarthritis is a slowly progressive disease that inevitably gets worse and results in increasing
pain and disability over time. However, the osteoarthritis process is one of attempted repair, and
this repair process may limit the damage and symptoms in many cases.
The need to consider osteoarthritis of the knee, hip and hand as separate entities is apparent from
their different natural histories and outcomes. Hand osteoarthritis has a particularly good prognosis.
Most cases of interphalangeal joint osteoarthritis become asymptomatic after a few years, although
patients are left with permanent swellings of the distal or proximal interphalangeal joints (called

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Osteoarthritis
Introduction
Heberden’s and Bouchard’s nodes respectively). Involvement of the thumb base may have a worse
prognosis, as in some cases this causes continuing pain on certain activities (such as pinch grip), and
thus lasting disability.
Knee osteoarthritis is very variable in its outcome. Improvement in the structure of the joint, as
shown by radiographs, is rare once the condition has become established. However, improvement in
pain and disability over time is common. The data on clinical outcomes, as opposed to radiographic
changes, is sparse, but it would seem that over a period of several years about a third of cases
improve, a third stay much the same, and the remaining third of patients develop progressive
symptomatic disease. Little is known about the risk factors for progression, which may be different
from those for initiation of the disease, but obesity probably makes an important contribution.
Hip osteoarthritis probably has the worst overall outcome of the three major sites considered in this
guideline. As with the knee, relatively little is known about the natural history of symptomatic
disease, but we do know that a significant number of people progress to a point where hip
replacement is needed in 1 to 5 years. In contrast, some hips heal spontaneously, with improvement
in the radiographic changes as well as the symptoms.
Osteoarthritis predominantly affects older people, and often co-exists with other conditions
associated with aging and obesity, such as cardiovascular disease and diabetes, as well as with
common sensory (for example, poor vision) and psychosocial problems (for example, anxiety,
depression and social isolation). The prognosis and outcome depends on these co-morbidities as
much as it does on the joint disease.
1.5 The impact on the individual

Osteoarthritis is the most common cause of disability in the UK. Pain, stiffness, joint deformity and
loss of joint mobility have a substantial impact on individuals.
Pain is the commonest reason for patients to present to their GP and over half the people with
osteoarthritis say that pain is their worse problem. Many people with osteoarthritis experience
persistent pain.15 Severity of pain is also important, with the likelihood of mobility problems
increasing as pain increases.494 It can affect every aspect of a person’s daily life, and overall quality of
life.120
“I mean, if I sit too long, that doesn’t help either. But the worst part is if I’m asleep and my legs are
bent and I haven’t woke up, the pain, I can’t tell you what it is like. I can not move it…and what I do is
I grip both hands round the knee and try to force my leg straight and I break out in a hot sweat. All I
can say is that it is a bony pain. I could shout out with the pain.”220
Osteoarthritis of the large joints reduces people’s mobility. Osteoarthritis accounts for more trouble
with climbing stairs and walking than any other disease.141 Furthermore, 80% of people with this
condition have some degree of limitation of movement and 25% cannot perform their major
activities of daily life.502 In small joints such as the hands and fingers osteoarthritis makes many
ordinary tasks difficult and painful.13
“When it first happened [knee pain], I couldn’t put weight on my foot. It was horrible. I can’t tell you
what it was like. Really really severe….painful; absolutely painful. I used to walk a lot, that stopped
me from walking, but now I’m walking again so that’s better isn’t it? I thought I’d be a cripple for life.
I couldn’t see it going. I couldn’t see what would make it go, but physio helped and those tablets
helped.”220
Older adults with joint pain are more likely to have participation restriction in areas of life such as
getting out and about, looking after others and work than those without joint pain.493 Although it is

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Introduction
difficult to be certain from studies of elderly populations with significant co-morbid medical
problems, it may be that there is an increased mortality associated with multiple-joint osteoarthritis.
1.6 The impact on society

Increases in life expectancy and ageing populations are expected to make osteoarthritis the fourth
leading cause of disability by the year 2020.321,501
 Osteoarthritis was estimated to be the eighth leading non-fatal burden of disease in the world in
1990, accounting for 2.8% of total years of living with disability, around the same percentage as
schizophrenia and congenital anomalies321,501
 Osteoarthritis was the sixth leading cause of years living with disability at a global level,
accounting for 3% of the total global years of living with disability501
Osteoarthritis has considerable impact on health services:

 Two million adults per year visit their GP due to osteoarthritis.15
 Consultations for osteoarthritis accounted for 15% of all musculoskeletal consultations in those
aged 45 years and over, peaking at 25% in those aged 75 years and over. Of those aged over 45
years, 5% have an osteoarthritis recorded primary care consultation in the course of a year. This
rises to 10% in those aged 75 years and over.223
 The incidence of a new GP consultation for knee pain in adults aged 50 and over is approximately
10% per year.224
 Over a one-year period there were 114,500 hospital admissions.15
 In 2000, over 44,000 hip replacements and over 35,000 knee replacements were performed at a
cost of £405 million.
Although some people do consult their GP, many others do not. In a recent study, over half of people
with severe and disabling knee pain had not visited their GP about this in the last 12 months.
People's perception of osteoarthritis is that it is a part of normal ageing. The perception that 'nothing
can be done' is a dominant feature in many accounts.399
Osteoarthritis has a significant negative impact on the UK economy, with its total cost estimated as
equivalent of 1% of GNP per year.13,119,120,262 Only a very few people who are receiving incapacity
benefit, – around one in 200 – later return to work.13,15 In 1999-2000, 36 million working days were
lost due to osteoarthritis alone, at an estimated cost of £3.2 billion in lost production. At the same
time, £43 million was spent on community services and £215 million were spent on social services
due to osteoarthritis.
1.7 Features of the evidence base for osteoarthritis

The following guidelines and recommendations for osteoarthritis are based on an evidence-based
appraisal of a vast amount of literature as well as on expert opinion, especially where the evidence
Update 2014
base is particularly lacking.
Where appropriate these guidelines have focused on patient-centred outcomes (often patient
reported outcomes) concerning pain, function, stiffness and quality of life. Unfortunately, many
studies do not include a quality of life measure, and often the only non-pain outcomes reported may
be a generic health-related quality of life measure such as the SF36.
There are always limitations to the evidence on which such guidelines are based, and the
recommendations need to be viewed in light of these limitations, including:

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Osteoarthritis
Introduction
 The majority of the published evidence relates to osteoarthritis of the knee. We have tried to
highlight where the evidence pertains to an individual anatomical location, and have presented
these as related to knee, hip, hand or mixed sites.
 There are very limited data on the effects of combinations of therapies.
 Many trials have looked at single joint involvement when many patients have multiple joint
involvement which may alter the reported efficacy of a particular therapeutic intervention.
 There is a major problem interpreting the duration of efficacy of therapies, since many studies,
especially those including pharmacological therapies, are of short duration.
 Similarly, side-effects may only be detected after long-term follow-up; where possible therefore
we have included toxicity data from long-term observational studies as well as randomised trials.
Update 2014
 When looking at studies of pharmacological therapies, there is the complexity of comparing
different doses of drugs.
 Many studies do not reflect ‘real-life’ patient use of therapies or their adherence. Patients may
not use pharmacological therapies on a daily basis or at the full recommended dosages. As well,
the use of over-the-counter medications has not been well studied in osteoarthritis populations.
 Most studies have not included patients with very severe osteoarthritis (e.g. severely functional
compromised patients who cannot walk, or patients with severe structural damage such as grade
4 Kellgren Lawrence radiographic damage). This may limit the extrapolation of the reported
benefits of a therapy to these patients.
 Studies often include patients who are not at high risk of drug side-effects. Many studies have not
included very elderly patients.
 There is an inherent bias with time-related improvement in design of studies: there tends to be
better designs with more recent studies, and often with pharmaceutical company funding.

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Osteoarthritis
Development of the guideline
2 Development of the guideline

2.1 What is a NICE clinical guideline?
NICE clinical guidelines are recommendations for the care of individuals in specific clinical conditions
or circumstances within the NHS – from prevention and self-care through primary and secondary
care to more specialised services. We base our clinical guidelines on the best available research
evidence, with the aim of improving the quality of health care. We use predetermined and
systematic methods to identify and evaluate the evidence relating to specific review questions.
NICE clinical guidelines can:

 provide recommendations for the treatment and care of people by health professionals
 be used to develop standards to assess the clinical practice of individual health professionals
 be used in the education and training of health professionals
 help patients to make informed decisions
 improve communication between patient and health professional
While guidelines assist the practice of healthcare professionals, they do not replace their knowledge
and skills.
We produce our guidelines using the following steps:

 Guideline topic is referred to NICE from the Department of Health
 Stakeholders register an interest in the guideline and are consulted throughout the development
Update 2014
process.
 The scope is prepared by the National Clinical Guideline Centre (NCGC)
 The NCGC establishes a guideline development group
 A draft guideline is produced after the group assesses the available evidence and makes
recommendations
 There is a consultation on the draft guideline.
 The final guideline is produced.
The NCGC and NICE produce a number of versions of this guideline:

 the full guideline contains all the recommendations, plus details of the methods used and the
underpinning evidence
 the NICE guideline lists the recommendations
 the quick reference guide (QRG) presents recommendations in a suitable format for health
professionals
 information for the public (‘understanding NICE guidance’ or UNG) is written using suitable
language for people without specialist medical knowledge.
This version is the full version. The other versions can be downloaded from NICE at www.nice.org.uk
2.2 Who developed this guideline?

A multidisciplinary Guideline Development Group (GDG) comprising professional group members and
consumer representatives of the main stakeholders developed this guideline (see section on
Guideline Development Group Membership and acknowledgements).

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Osteoarthritis
The National Institute for Health and Care Excellence funds the National Clinical Guideline Centre
(NCGC) and thus supported the development of this guideline. The GDG was convened by the NCGC
and chaired by Professor Philip Conaghan in accordance with guidance from the National Institute for
Health and Care Excellence (NICE).
The group met every 6 weeks during the development of the guideline. At the start of the guideline
development process all GDG members declared interests including consultancies, fee-paid work,
share-holdings, fellowships and support from the healthcare industry. At all subsequent GDG
meetings, members declared arising conflicts of interest, which were also recorded (Appendix B).
Members were either required to withdraw completely or for part of the discussion if their declared
interest made it appropriate. The details of declared interests and the actions taken are shown in
Appendix B.
Staff from the NCGC provided methodological support and guidance for the development process.
The team working on the guideline included a project manager, systematic reviewers, health
economists and information scientists. They undertook systematic searches of the literature,
appraised the evidence, conducted Meta-analysis and cost effectiveness analysis where appropriate
and drafted the guideline in collaboration with the GDG.
2.3 What this guideline covers

Adults with a working diagnosis a of osteoarthritis will be covered in this guideline. For further details
please refer to the scope in Appendix A and review questions in section 3.1.
Update 2014
2.4 What this guideline does not cover
People with predisposing and associated conditions including:
 spinal, neck and back pain
 crystal arthritis (gout or pseudo-gout)
 inflammatory arthritis (including rheumatoid arthritis, psoriatic arthritis and the seronegative
arthritides)
 septic arthritis
 diseases of childhood that predispose to osteoarthritis
 medical conditions presenting with joint inflammation, such as haemochromatosis.
2.5 Relationships between the guideline and other NICE guidance

Details are correct at the time of consultation on the guideline (August 2013). Further information is
available on the NICE website.
Published
General
 Patient experience in adult NHS services. NICE clinical guidance 138 (2012).
 Medicines adherence. NICE clinical guidance 76 (2009).
a
A working diagnosis of osteoarthritis should include:
 persistent joint pain that becomes worse with use
 predominantly in people age 45 years or older
 morning stiffness lasting no more than half an hour.

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Condition-specific
 Minimally invasive total hip replacement. NICE interventional procedure guidance 363 (2010).
 Mini-incision surgery for total knee replacement. NICE interventional procedure guidance 345
(2010).
 Shoulder resurfacing arthroplasty. NICE interventional procedure guidance 354 (2010).
 Depression in adults with a chronic physical health problem. NICE clinical guideline 91 (2009).
 Total prosthetic replacement of the temporomandibular joint. NICE interventional procedure
guidance 329 (2009).
 Individually magnetic resonance imaging-designed unicompartmental interpositional implant
Update 2014
insertion for osteoarthritis of the knee. NICE interventional procedure guidance 317 (2009).
 Rheumatoid arthritis. NICE clinical guideline 79 (2009).
 Total wrist replacement. NICE interventional procedure guidance 271 (2008)
 Arthroscopic knee washout, with or without debridement, for the treatment of osteoarthritis.
NICE interventional procedure guidance 230 (2007).
 Obesity. NICE clinical guideline 43 (2006).
 Metatarsophalangeal joint replacement of the hallux. NICE interventional procedure guidance 140
(2005).
 Artificial trapeziometacarpal joint replacement for end-stage osteoarthritis. NICE interventional
procedure guidance 111 (2005).
 Artificial metacarpophalangeal and interphalangeal joint replacement for end-stage arthritis. NICE
interventional procedure guidance 110 (2005).

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Methods
3 Methods
The updated guidance was developed in accordance with the methods outlined in the NICE
Guidelines Manual 2009.327This is the case for the clinical and cost evidence presented in chapters 5,
12 and 13 and sections 7.2, 8.4, 8.5, and 10.2.
NICE methods have evolved since the development of CG59. A key change in this update is the focus
on the development of recommendations based on the consideration of which interventions make a
clinically important difference to patients rather than the statistical significance of the effect of an
intervention when compared to an appropriate comparison which CG59 applied. As such, because of
this difference in application of methodological approach, decisions have been made on different
thresholds between the recommendations from CG 59 and those made as part of this update. This
chapter outlines the methods used in this update and the methods used to develop CG59 can be
found in Appendix O.
3.1 Developing the review questions and outcomes

Review questions were developed in a PICO framework (patient, intervention, comparison and
outcome) for intervention reviews, and with a framework of population, index tests, reference
standard and target condition for reviews of diagnostic test accuracy. This was to guide the literature
searching process and to facilitate the development of recommendations by the guideline
development group (GDG). They were drafted by the NCGC technical team and refined and validated
by the GDG. The questions were based on the key clinical areas identified in the scope (Appendix A).
Further information on the outcome measures examined follows this section.
Update 2014
Table 2: Review questions for guideline update
Chapter Review questions Outcomes
Diagnosis In a person with suspected  Sensitivity
clinical OA (including knee  Specificity
pain)when would the addition
 Likelihood ratio
of imaging be indicated to
confirm additional or  Diagnostic accuracy
alternative diagnoses  Other clinical management outcomes (e.g.
(particularly to identify red referral)
flags) such as:
-Crystal arthritis (gout or

CPPD)
-Inflammatory arthritis
(including rheumatoid
arthritis, psoriatic arthritis)
-Infection
-Cancer, usually secondary
metastases
Acupuncture What is the clinical and cost  Global joint pain (WOMAC, VAS, or NRS pain
effectiveness of acupuncture subscale, WOMAC for knee and hip only,
versus sham treatment AUSCAN subscale for hand
(placebo) and other  Function (WOMAC function subscale for hip or
interventions in the knee or equivalent such as AUSCAN function
management of subscale or Cochin or FIHOA for hand and change
osteoarthritis? from baseline)
 Stiffness (WOMAC stiffness score change from

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Methods

baseline)
 Time to joint replacement
 Quality of life (EQ5D, SF 36)
 Patient global assessment
 OARSI responder criteria
 Adverse events
 Measure Yourself Medical Outcome Profile
Nutraceuticals What is the clinical and cost  Global joint pain (VAS, NRS or WOMAC pain
effectiveness of glucosamine subscale, WOMAC for knee and hip only,
and chondroitin alone or in AUSCAN subscale for hand
compound form versus  Function (WOMAC function subscale for hip or
placebo or other treatments knee or equivalent such as AUSCAN function
in the management of subscale or Cochin or FIHOA for hand and change
osteoarthritis? from baseline)
baseline)
 Structure modification
 Adverse events (GI, renal and cardiovascular)
Update 2014
Hyaluronan What is the clinical and cost  Global joint pain (VAS or NRS, WOMAC pain
Injections effectiveness of intra-articular subscale, WOMAC for knee and hip only,
injections of hyaluronic acid/ AUSCAN for hand)*
hyaluronans in the  Function (WOMAC function subscale for hip or
management of OA in the knee or equivalent such as AUSCAN function
knee, hand, ankle, big toe and subscale and change from baseline)
hip?
baseline)
 Minimum joint space width
 Quality of life (EQ5D, SF 36)*
 Adverse events*
 -post injection flare
Decision-aids What is the clinical and cost-  Attributes of the choice
effectiveness of decision aids  Attributes of the decision making process
in the management of OA?
 Decisional conflict
 Patient-practitioner communication
 Participation in decision making
 Proportion undecided
 Satisfaction
 Choice (actual choice implemented, option
preferred as surrogate measure)
 Adherence to chosen option
 Health status and quality of life (generic and
condition specific)

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Methods

 Anxiety, depression, emotional distress, regret,
confidence
 Consultation length
Follow-up What is the clinical and cost  Global joint pain (WOMAC, VAS, or NRS pain
effectiveness of regular subscale, WOMAC for knee and hip only,
follow-up/review in AUSCAN subscale for hand
reinforcing core treatments  Function (WOMAC function subscale for hip or
(information, education, knee or equivalent such as AUSCAN function
exercise, weight reduction) subscale or Cochin or FIHOA for hand and change
care in the management of from baseline)
OA?
Which patients with OA will baseline)
benefit the most from
reinforcement of core
treatment as part of regular  Quality of life (EQ5D, SF 36)
follow-up/review?  Patient global assessment
 Improvement in depression/ psychological
outcomes
Timing of What information should  Patient views/experiences
surgery people with OA receive to  Patient preference/satisfaction
inform consideration of the
 Patient knowledge
appropriate timing of referral
for surgery as part of their OA
Update 2014
management?
3.2 Searching for evidence

3.2.1 Clinical literature search
Systematic literature searches were undertaken in accordance with the Guidelines Manual 2012327 to
identify evidence within published literature in order to answer the review questions. Clinical
databases were searched using relevant medical subject headings, free-text terms and study type
filters where appropriate. Studies published in languages other than English were not reviewed.
Where possible, searches were restricted to articles published in the English language. All searches
were conducted on three core databases: Medline, Embase and the Cochrane Library. An additional
subject specific database (Allied and Complementary Medicine database) was used for the question
on acupuncture. All searches were updated on 7th May 2013. No papers added to the above
databases after this date were considered.
Search strategies were checked by looking at reference lists of relevant key papers, checking search
strategies in other systematic reviews and asking the GDG for known studies. The questions, the
study type filters applied, the databases searched and the years covered can be found in Appendix F.
During the scoping stage, a search was conducted for guidelines and reports on the websites listed
below and on organisations relevant to the topic. Searching for grey literature or unpublished
literature was not undertaken. All references sent by stakeholders were considered.
 Guidelines International Network database (www.g-i-n.net)
 National Guideline Clearing House (www.guideline.gov)
 NHS Evidence (www.evidence.nhs.uk)
 Clinical Evidence (clinicalevidence.bmj.com)

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Methods
 UK Database of Uncertainties about the Effects of Treatments (UK DUETs)

(www.library.nhs.uk/duets)
 Centre for Reviews and Dissemination Health Technology Appraisals database (CRD HTA)
(www.crd.york.ac.uk/crdweb)
3.2.2 Health economic literature search

Systematic literature searches were also undertaken to identify health economic evidence within
published literature relevant to the review questions. The evidence was identified by conducting a
broad search relating to osteoarthritis in the NHS economic evaluation database (NHS EED), the
Health Economic Evaluations Database (HEED) and health technology assessment (HTA) databases
from 2007, the date of searches conducted for the previous osteoarthritis guideline.322 Additionally,
the search was run on Medline and Embase, with an economic filter, from 2010, to ensure recent
publications that had not yet been indexed by the health economics databases were identified.
Studies published in languages other than English were not reviewed. Where possible, searches were
restricted to articles published in English language.
The search strategies for health economics are included in Appendix F. All searches were updated on
7th May 2013. No papers published after this date were considered.
3.3 Evidence of effectiveness

The Research Fellow:
Identified potentially relevant studies for each review question from the relevant search results by
Update 2014
reviewing titles and abstracts – full papers were then obtained.
Reviewed full papers against pre-specified inclusion / exclusion criteria to identify studies that
addressed the review question in the appropriate population and reported on outcomes of interest
(review protocols are included in Appendix C).
Critically appraised relevant studies using the appropriate checklist as specified in The Guidelines
Manual 2012. 327
Extracted key information about the study’s methods and results into evidence tables (evidence
tables are included in Appendix G).
 Generated summaries of the evidence by outcome (included in the relevant chapter write-ups):
o Randomised studies: meta analysed, where appropriate and reported in GRADE profiles (for
clinical studies) – see below for details
o Observational studies: data presented as a range of values in GRADE profiles
o Diagnostic studies: data presented as a range of values in adapted GRADE profiles
o Qualitative studies: each study summarised in a table where possible, otherwise presented in a
narrative.
3.3.1 Inclusion/exclusion
See the review protocols in Appendix C for full details.
The guideline population was defined to be adults with osteoarthritis.
The temporomandibular joint was excluded as this is an area predominantly managed by dentists
and dental specialists and not the target audience of this guideline

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Methods
Shoulders were excluded because the vast majority of shoulder pain is not due to OA but to
tendonitis and bursitis problems. The GDG also pointed out that the number of studies in true
shoulder OA is very small.
Spine and back were excluded because there are other NICE guidelines looking at back pain. The back
pain literature is extensive and separate from the OA literature.
Randomised trials, non-randomised trials, and observational studies were included in the evidence
reviews as appropriate. Conference abstracts were not automatically excluded from the review but
were initially assessed against the inclusion criteria and then further processed only if no other full
publication was available for that review question, in which case the authors of the selected
abstracts were contacted for further information. Conference abstracts included in Cochrane reviews
were included when they met the review inclusion criteria and authors were not contacted.
Literature reviews, letters and editorials, foreign language publications and unpublished studies were
excluded.
3.3.2 Methods of combining clinical studies
Data synthesis for intervention reviews
Where possible, meta-analyses were conducted to combine the results of studies for each review
question using Cochrane Review Manager (RevMan5) software. Fixed-effects (Mantel-Haenszel)
techniques were used to calculate risk ratios (relative risk) for the binary outcomes: OARSI
responder criteria; adverse events; and withdrawal from trial.The continuous outcomes (global joint
pain; function; stiffness; time to joint replacement; patient global assessment and quality of life)
Update 2014
were analysed using an inverse variance method for pooling weighted mean differences and due to
different sub-scales in studies, standardised mean differences were used on the advice of the GDG.
Final values were reported where available for continuous outcomes in preference of change scores.
However, if change scores only were available, these were reported and meta-analysed with final
values. Stratified analyses were predefined for some review questions at the protocol stage when the
GDG identified that these strata were expected to show a different effect (e.g. differences in efficacy
of interventions when used for differing joints e.g. knee, hip, ankle etc.).
Statistical heterogeneity was assessed by considering the chi-squared test for significance at p<0.1 or
an I-squared inconsistency statistic of >50% to indicate significant heterogeneity. Where significant
heterogeneity was present, we carried out predefined subgroup analyses (e.g. in acupuncture
including only trials with adequate blinding, please see individual protocols in appendix C for further
details).
Assessments of potential differences in effect between subgroups were based on the chi-squared
tests for heterogeneity statistics between subgroups. If no sensitivity analysis was found to
completely resolve statistical heterogeneity then a random effects (DerSimonian and Laird) model
was employed to provide a more conservative estimate of the effect.
The means and standard deviations of continuous outcomes were required for meta-analysis.
However, in cases where standard deviations were not reported, the standard error was calculated if
the p-values or 95% confidence intervals were reported and meta-analysis was undertaken with the
mean and standard error using the generic inverse variance method in Cochrane Review Manager
(RevMan5) software. Where p values were reported as “less than”, a conservative approach was
undertaken. For example, if p value was reported as “p ≤0.001”, the calculations for standard
deviations will be based on a p value of 0.001. If these statistical measures were not available then
the methods described in section 16.1.3 of the Cochrane Handbook (September 2009) ‘Missing
standard deviations’ were applied as the last resort.

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For binary outcomes, absolute event rates were also calculated using the GRADEpro software using
event rate in the control arm of the pooled results.
Data synthesis for diagnostic test accuracy review
For diagnostic test accuracy studies, the following outcomes were reported: sensitivity, specificity,
positive predictive value, negative predictive value, likelihood ratio and correlations/associations
between clinical and radiological features. In cases where the outcomes were not reported, 2 by 2
tables were constructed from raw data to allow calculation of these accuracy measures.
3.3.3 Appraising the quality of evidence by outcomes
The international consensus group OMERACT (Outcome measures in Rheumatology), using a process
involving patients, recommended that pain, physical function and patient global assessment should
be core outcome measures for OA clinical trials. Pain is also prioritised by patients and other
international groups. Patient global assessment is assessed using a wide variety of tools, whereas
pain and function outcomes are commonly collected using a more restricted number of tools,
especially the WOMAC instrument, which also captures the lesser prioritised domain of stiffness. The
GDG agreed therefore that the critical outcomes for decision-making for the intervention evidence
reviews were: joint pain, function, and stiffness. The GDG agreed that joint pain was the most
important outcome to assess analgesic effect.
The following outcomes were also considered important to decision-making: quality of life, OARSI
responder criteria, adverse events, withdrawal from trial, time to joint replacement, and patient
Update 2014
global assessment .
The evidence for outcomes from the included RCT and observational studies were evaluated and
presented using an adaptation of the ‘Grading of Recommendations Assessment, Development and
Evaluation (GRADE) toolbox’ developed by the international GRADE working group
(http://www.gradeworkinggroup.org/). The software (GRADEpro) developed by the GRADE working
group was used to assess the quality of each outcome, taking into account individual study quality
and the meta-analysis results. The summary of findings was presented as two separate tables in this
guideline. The “Clinical/Economic evidence profile” table includes details of the quality assessment
while the “Clinical /Economic evidence summary of Findings” table includes pooled outcome data,
where appropriate, an absolute measure of intervention effect and the summary of quality of
evidence for that outcome. In this table, the columns for intervention and control indicate the sum of
the sample size for continuous outcomes. For binary outcomes such as number of patients with an
adverse event, the event rates (n/N: number of patients with events divided by sum of number of
patients) are shown with percentages. Reporting or publication bias was only taken into
consideration in the quality assessment and included in the Clinical evidence profile table if it was
apparent. This was taken into consideration for randomised trial evidence in the the review of
paracetamol versus placbo.
Each outcome was examined separately for the quality elements listed and defined in Table 3 and
each graded using the quality levels listed in Table 4. The main criteria considered in the rating of
these elements are discussed below (see section 3.3.4 Grading of Evidence). Footnotes were used to
describe reasons for grading a quality element as having serious or very serious problems. The
ratings for each component were summed to obtain an overall assessment for each outcome.
Table 3: Description of quality elements in GRADE for intervention studies

Quality element Description
Limitations Limitations in the study design and implementation may bias the estimates of the

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Quality element Description

treatment effect. Major limitations in studies decrease the confidence in the estimate
of the effect.
Inconsistency Inconsistency refers to an unexplained heterogeneity of results.
Indirectness Indirectness refers to differences in study population, intervention, comparator and
outcomes between the available evidence and the review question, or
recommendation made.
Imprecision Results are imprecise when studies include relatively few patients and few events and
thus have wide confidence intervals around the estimate of the effect relative to the
clinically important threshold.
Publication bias Publication bias is a systematic underestimate or an overestimate of the underlying
beneficial or harmful effect due to the selective publication of studies.
Table 4: Levels of quality elements in GRADE

Level Description
None There are no serious issues with the evidence
Serious The issues are serious enough to downgrade the outcome evidence by one level
Very serious The issues are serious enough to downgrade the outcome evidence by two levels
Table 5: Overall quality of outcome evidence in GRADE

Level Description
Update 2014
High Further research is very unlikely to change our confidence in the estimate of effect
Moderate Further research is likely to have an important impact on our confidence in the estimate
of effect and may change the estimate
Low Further research is very likely to have an important impact on our confidence in the
estimate of effect and is likely to change the estimate
Very low Any estimate of effect is very uncertain
3.3.4 Grading the quality of clinical evidence

After results were pooled, the overall quality of evidence for each outcome was considered. The
following procedure was adopted when using GRADE:
1. A quality rating was assigned, based on the study design. RCTs start HIGH and observational
studies as LOW, uncontrolled case series as LOW or VERY LOW.
2. The rating was then downgraded for the specified criteria: Study limitations, inconsistency,
indirectness, imprecision and reporting bias. These criteria are detailed below. Observational
studies were upgraded if there was: a large magnitude of effect, dose-response gradient, and if all
plausible confounding would reduce a demonstrated effect or suggest a spurious effect when
results showed no effect. Each quality element considered to have “serious” or “very serious” risk
of bias was rated down -1 or -2 points respectively.
3. The downgraded/upgraded marks were then summed and the overall quality rating was revised.
For example, all RCTs started as HIGH and the overall quality became MODERATE, LOW or VERY
LOW if 1, 2 or 3 points were deducted respectively.
4. The reasons or criteria used for downgrading were specified in the footnotes.
The details of criteria used for each of the main quality element are discussed further in the following
sections 3.3.5 to 3.3.8.

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3.3.5 Study limitations

The main limitations for randomised controlled trials are listed in Table 6.
Table 6: Study limitations of randomised controlled trials

Limitation Explanation
Allocation Those enrolling patients are aware of the group to which the next enrolled patient
concealment will be allocated (major problem in “pseudo” or “quasi” randomised trials with
allocation by day of week, birth date, chart number, etc)
Lack of blinding Patient, caregivers, those recording outcomes, those adjudicating outcomes, or data
analysts are aware of the arm to which patients are allocated
Incomplete Loss to follow-up not accounted and failure to adhere to the intention to treat
accounting of principle when indicated
patients and
outcome events
Selective outcome Reporting of some outcomes and not others on the basis of the results
reporting
Other limitations For example:
 Stopping early for benefit observed in randomised trials, in particular in the absence
of adequate stopping rules
 Use of unvalidated patient-reported outcomes
 Carry-over effects in cross-over trials
 Recruitment bias in cluster randomised trials
Update 2014
3.3.6 Inconsistency
Inconsistency refers to an unexplained heterogeneity of results. When estimates of the treatment
effect across studies differ widely (i.e. heterogeneity or variability in results), this suggests true
differences in underlying treatment effect. When heterogeneity exists (Chi square p<0.1 or I- squared
inconsistency statistic of >50%), but no plausible explanation can be found, the quality of evidence
was downgraded by one or two levels, depending on the extent of uncertainty to the results
contributed by the inconsistency in the results. In addition to the I- square and Chi square values, the
decision for downgrading was also dependent on factors such as whether the intervention is
associated with benefit in all other outcomes or whether the uncertainty about the magnitude of
benefit (or harm) of the outcome showing heterogeneity would influence the overall judgment about
net benefit or harm (across all outcomes).
3.3.7 Indirectness
Directness refers to the extent to which the populations, intervention, comparisons and outcome
measures are similar to those defined in the inclusion criteria for the reviews. Indirectness is
important when these differences are expected to contribute to a difference in effect size, or may
affect the balance of harms and benefits considered for an intervention.
3.3.8 Imprecision
Imprecision in guidelines concerns whether the uncertainty (confidence interval) around the effect
estimate means that we don’t know whether there is a clinically important difference between
interventions. Therefore, imprecision differs from the other aspects of evidence quality, in that it is
not really concerned with whether the point estimate is accurate or correct (has internal or external
validity) instead we are concerned with the uncertainty about what the point estimate is. This
uncertainty is reflected in the width of the confidence interval.

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The 95% confidence interval is defined as the range of values that contain the population value with
95% probability. The larger the trial, the smaller the confidence interval and the more certain we are
in the effect estimate.
Imprecision in the evidence reviews was assessed by considering whether the width of the
confidence interval of the effect estimate is relevant to decision making, considering each outcome
in isolation. Figure 1 considers a positive outcome for the comparison of treatment A versus B. Three
decision making zones can be identified, bounded by the thresholds for clinical importance (Minimal
important difference, [MID]) for benefit and for harm (the MID for harm for a positive outcome
means the threshold at which drug A is less effective than drug B and this difference is clinically
important to patients (favours B).
Figure 1: Imprecision illustration
Update 2014
Source: Figure adapted from GRADEPro software.
 When the confidence interval of the effect estimate is wholly contained in one of the three zones
(e.g. clinically important benefit), we are not uncertain about the size and direction of effect
(whether there is a clinically important benefit or the effect is not clinically important or there is a
clinically important harm), so there is no imprecision.
 When a wide confidence interval lies partly in each of two zones, it is uncertain in which zone the
true value of effect estimate lies, and therefore there is uncertainty over which decision to make
(based on this outcome alone); the confidence interval is consistent with two decisions and so this
is considered to be imprecise in the GRADE analysis and the evidence is downgraded by one
(“serious imprecision”).
 If the confidence interval of the effect estimate crosses into three zones, this is considered to be
very imprecise evidence because the confidence interval is consistent with three clinical decisions
and there is a considerable lack of confidence in the results. The evidence is therefore
downgraded by two in the GRADE analysis (“very serious imprecision”).
 Implicitly, assessing whether the confidence interval is in, or partially in, a clinically important
zone, requires the GDG to estimate an MID or to say whether they would make different
decisions for the two confidence limits.
The literature was searched for established MIDs for the selected outcomes in the evidence reviews.
The following studies were retrieved and reviewed by the GDG:
 Revicki 2008381
 Pham 2003360
 Tubach 2005462

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The Revicki 2008 study summarised information on evaluating responsiveness and generation of MID
estimates in general for patient reported outcomes not specific to OA.
The Pham 2003 study concerned the generation of the OMERACT-OARSI responder criteria, a
composite outcome of pain, function and patient global assessment. The GDG selected this as an
important outcome and where reported has been included throughout the guideline.
The Tubach 2005 study calculated MIDs for WOMAC function which corresponded to SMDs of 0.33
(knee OA) and 0.16 (hip OA). Patients rated an improvement in their pain symptoms of 0.67 SMD
(knee OA) or 0.44 SMD (hip OA) as “good”. The GDG agreed not to use the MIDs proposed in the
Tubach 2005 study.The group consensus was that the Tubach MIDs were challenging to use in the
context of clinical guideline development as they were developed for an individual RCT and would
not be appropriate for the purposes of meta-analysis in guideline development. The GDG felt that we
should not routinely be using MIDs from single research studies for decision-making. Current NICE
guidance is that the best source of an MID for use in clinical decision making is a systematic review of
the evidence or an international consensus statement that is established within the relevant clinical
community. Established MIDs are likely to be published widely and should be seen and accepted and
utilised by that community. As well as a review of the literature relating to MIDs for the OA field the
GDG was asked whether they were aware of any acceptable MIDs in the clinical community of
osteoarthritis but they confirmed the lack of international consensus on specific thresholds for the
selected outcomes. The GDG was aware of work being done in this area, in particular planned work
by OMERACT in 2014 but felt that MIDs were not as yet established for use in this clinical guideline.
As there are no validated MIDs for SMDs, the GDG agreed to use the empirical cut-off suggested by
the GRADE working group as part of the NICE methodological process. Therefore, the GDG agreed to
Update 2014
use the following GRADE default thresholds to assess imprecision, the MID of 0.5 SMD for continuous
outcomes; and 25% relative risk reduction or relative risk increase, which corresponds to a RR
clinically important threshold of 0.75 or 1.25 respectively, for binary outcomes. These default MIDs
were used for all the outcomes in across the evidence reviews.
The GDG accepted that there are limitations of applying an MID of 0.5 SMD. They acknowledged that
there are very few interventions for OA that would reach this cut off for clinical effectiveness.
However there was limited published or international consensus evidence available to provide firm
cut-offs. An MID of 0.2 SMD was also considered when weighing up individual therapy benefits. For
a few therapies, occasional results changed from an intervention being similarly effective to being
more clinically effective but all still demonstrated uncertainty.
The GDG also agreed to draft a research recommendation on minimal important differences (MID)
for the main clinical outcomes in OA because of the challenges in this area. Further details on the
research recommendations can be found in appendix N.
Assessing clinical importance
The GDG assessed the evidence by outcome in order to determine if there was, or was potentially, a
clinically important benefit, a clinically important harm or no clinically important difference between
interventions.
The assessment of benefit/harm/no benefit or harm was based on the point estimate of the
standardised mean difference for intervention studies which was standardized across the reviews
and against the MID thresholds described above. This assessment was carried out by the GDG for
each outcome. The GDG used the assessment of clinical importance for the outcomes alongside the
evidence quality and the uncertainty in the effect estimates to make an overall judgement on the
balance of benefit and harms of an intervention.

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Publication bias
Downgrading for publication bias would only be carried out if the GDG were aware that there was
serious publication bias for that particular outcome. Such downgrading was not carried out for this
guideline.
Evidence statements
Evidence statements are summary statements that are presented after the GRADE profiles,
summarizing the key features of the clinical effectiveness evidence presented. The wording of the
evidence statements reflects the certainty/uncertainty in the estimate of effect. The evidence
statements are presented by outcome and encompass the following key features of the evidence:
 The number of studies and the number of participants for a particular outcome.
 An indication of the direction of clinical importance (if one treatment is beneficial or harmful
compared to the other, or whether there is no difference between two tested treatments).
3.4 Evidence of cost-effectiveness

The GDG is required to make decisions based on the best available evidence of both clinical and cost
effectiveness. Guideline recommendations should be based on the expected costs of the different
options in relation to their expected health benefits (that is, their ‘cost effectiveness’) rather than the
total implementation cost.327 Thus, if the evidence suggests that a strategy provides significant health
benefits at an acceptable cost per patient treated, it should be recommended even if it would be
expensive to implement across the whole population.
Update 2014
Evidence on cost-effectiveness related to the key clinical issues being addressed in the guideline was
sought. The health economist undertook:
 A systematic review of the published economic literature.
 New cost-effectiveness analysis in priority areas.
3.4.1 Literature review

The health economist:
 Identified potentially relevant studies for each review question from the economic search results
by reviewing titles and abstracts – full papers were then obtained.
 Reviewed full papers against pre-specified inclusion / exclusion criteria to identify relevant studies
(see below for details).
 Critically appraised relevant studies using the economic evaluations checklist as specified in The
Guidelines Manual. 327
 Extracted key information about the studies’ methods and results into evidence tables (included
in Appendix H).
 Generated summaries of the evidence in NICE economic evidence profiles (included in the
relevant chapter write-ups) – see below for details.
3.4.1.1 Inclusion/exclusion
Full economic evaluations (studies comparing costs and health consequences of alternative courses
of action: cost–utility, cost-effectiveness, cost-benefit and cost-consequence analyses) and
comparative costing studies that addressed the review question in the relevant population were
considered potentially includable as economic evidence.

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Methods
Studies that only reported cost per hospital (not per patient), or only reported average cost
effectiveness without disaggregated costs and effects, were excluded. Abstracts, posters, reviews,
letters/editorials, foreign language publications and unpublished studies were excluded. Studies
judged to have an applicability rating of ‘not applicable’ were excluded (this included studies that
took the perspective of a non-OECD country).
Remaining studies were prioritised for inclusion based on their relative applicability to the
development of this guideline and the study limitations. For example, if a high quality, directly
applicable UK analysis was available other less relevant studies may not have been included. Where
exclusions occurred on this basis, this is noted in the relevant section.
For more details about the assessment of applicability and methodological quality see the economic
evaluation checklist (The Guidelines Manual, 327 and the health economics research protocol in
Appendix C).
3.4.1.2 NICE economic evidence profiles
The NICE economic evidence profile has been used to summarise cost and cost-effectiveness
estimates. The economic evidence profile shows, for each economic study, an assessment of
applicability and methodological quality, with footnotes indicating the reasons for the assessment.
These assessments were made by the health economist using the economic evaluation checklist from
The Guidelines Manual.327. It also shows incremental costs, incremental effects (for example, quality-
adjusted life years [QALYs]) and the incremental cost-effectiveness ratio, as well as information
about the assessment of uncertainty in the analysis. See Table 7 for more details.
Update 2014
If a non-UK study was included in the profile, the results were converted into pounds sterling using
the appropriate purchasing power parity.336
Table 7: Content of NICE economic profile

Item Description
Study First author name, reference, date of study publication and country perspective.
Applicability An assessment of applicability of the study to the clinical guideline, the current NHS
situation and NICE decision-making*:
 Directly applicable – the applicability criteria are met, or one or more criteria are
not met but this is not likely to change the conclusions about cost effectiveness.
 Partially applicable – one or more of the applicability criteria are not met, and this
might possibly change the conclusions about cost effectiveness.
Not applicable – one or more of the applicability criteria are not met, and this is
likely to change the conclusions about cost effectiveness.
Limitations An assessment of methodological quality of the study*:
 Minor limitations – the study meets all quality criteria, or the study fails to meet
one or more quality criteria, but this is unlikely to change the conclusions about
cost effectiveness.
 Potentially serious limitations – the study fails to meet one or more quality
criteria, and this could change the conclusion about cost effectiveness
 Very serious limitations – the study fails to meet one or more quality criteria and
this is very likely to change the conclusions about cost effectiveness. Studies with
very serious limitations would usually be excluded from the economic profile
table.
Other comments Particular issues that should be considered when interpreting the study.
Incremental cost The mean cost associated with one strategy minus the mean cost of a comparator
strategy.
Incremental effects The mean QALYs (or other selected measure of health outcome) associated with

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Methods
Item Description
one strategy minus the mean QALYs of a comparator strategy.
Cost effectiveness Incremental cost-effectiveness ratio (ICER): the incremental cost divided by the
incremental effects.
Uncertainty A summary of the extent of uncertainty about the ICER reflecting the results of
deterministic or probabilistic sensitivity analyses, or stochastic analyses of trial data,
as appropriate.
*Applicability and limitations were assessed using the economic evaluation checklist from The Guidelines
327
Manual.
3.4.2 Undertaking new health economic analysis

As well as reviewing the published economic literature for each review question, as described above,
new economic analysis was undertaken by the health economist in selected areas. Priority areas for
new health economic analysis were agreed by the GDG after formation of the review questions and
consideration of the available health economic evidence.
The GDG identified oral NSAIDs/COX-2 inhibitors as the highest priority area for original economic
modelling. The GDG felt that updating the CG59 model was a priority in order to incorporate the
updated review data on the effectiveness and adverse events of paracetamol, and also to include the
fixed dose combination pills..
The following general principles were adhered to in developing the cost-effectiveness analysis:
 Methods were consistent with the NICE reference case.325.
Update 2014
 The GDG was involved in the design of the model, selection of inputs and interpretation of the
results.
 Model inputs were based on the systematic review of the clinical literature supplemented with
other published data sources where possible.
 When published data was not available GDG expert opinion was used to populate the model.
 Model inputs and assumptions were reported fully and transparently.
 The results were subject to sensitivity analysis and limitations were discussed.
 The model was peer-reviewed by another health economist at the NCGC.
Full methods for the cost-effectiveness analysis for oral NSAIDs/COX-2 inhibitors are described in
Appendix L.
3.4.3 Cost-effectiveness criteria

NICE’s report ‘Social value judgements: principles for the development of NICE guidance’ sets out the
principles that GDGs should consider when judging whether an intervention offers good value for
money.326,327In general, an intervention was considered to be cost effective if either of the following
criteria applied (given that the estimate was considered plausible):
a. The intervention dominated other relevant strategies (that is, it was both less costly in terms of
resource use and more clinically effective compared with all the other relevant alternative
strategies), or
b. The intervention cost less than £20,000 per QALY gained compared with the next best strategy.
If the GDG recommended an intervention that was estimated to cost more than £20,000 per QALY
gained, or did not recommend one that was estimated to cost less than £20,000 per QALY gained,
the reasons for this decision are discussed explicitly in the ‘from evidence to recommendations’
section of the relevant chapter with reference to issues regarding the plausibility of the estimate or
to the factors set out in the ‘Social value judgements: principles for the development of NICE

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Osteoarthritis
Methods
guidance’.326 When QALYs or life years gained are not used in the analysis, results are difficult to
interpret unless one strategy dominates the others with respect to every relevant health outcome
and cost.
3.4.4 In the absence of economic evidence

When no relevant published studies were found, and a new analysis was not prioritised, the GDG
made a qualitative judgement about cost effectiveness by considering expected differences in
resource use between options and relevant UK NHS unit costs alongside the results of the clinical
review of effectiveness evidence.
3.5 Developing recommendations

Over the course of the guideline development process, the GDG was presented with:
 Evidence tables of the clinical and economic evidence reviewed from the literature. All evidence
tables are in Appendices G and H.
 Summary of clinical and economic evidence and quality (as presented in chapters 5 to 13)
 Forest plots and summary ROC curves (Appendix I)
 A description of the methods and results of the cost-effectiveness analysis undertaken for the
guideline (Appendix L)
Recommendations were drafted on the basis of the GDG interpretation of the available evidence,
taking into account the balance of benefits, harms and costs. When clinical and economic evidence
Update 2014
was of poor quality, conflicting or absent, the GDG drafted recommendations based on their expert
opinion. The considerations for making consensus based recommendations include the balance
between potential harms and benefits, economic or implications compared to the benefits, current
practices, recommendations made in other relevant guidelines, patient preferences and equality
issues. The consensus recommendations were done through discussions in the GDG.The main
considerations specific to each recommendation are outlined in the Evidence to Recommendation
Section preceding the recommendation section.
3.5.1 Research recommendations

When areas were identified for which good evidence was lacking, the guideline development group
considered making recommendations for future research. Decisions about inclusion were based on
factors such as:
 the importance to patients or the population
 national priorities
 potential impact on the NHS and future NICE guidance
 ethical and technical feasibility
3.5.2 Validation process

The guidance is subject to a six week public consultation for feedback as part of the quality assurance
and peer review of the document. All comments received from registered stakeholders are
responded to in turn and posted on the NICE website when the the full guideline is published.

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Methods
3.5.3 Updating the guideline

A formal review of the need to update a guideline is usually undertaken by NICE after its publication.
NICE will conduct a review to determine whether the evidence base has progressed significantly to
alter the guideline recommendations and warrant an update.
3.5.4 Disclaimer
Update 2014
Health care providers need to use clinical judgement, knowledge and expertise when deciding
whether it is appropriate to apply guidelines. The recommendations cited here are a guide and may
not be appropriate for use in all situations. The decision to adopt any of the recommendations cited
here must be made by the practitioners in light of individual patient circumstances, the wishes of the
patient, clinical expertise and resources.
The National Clinical Guideline Centre disclaims any responsibility for damages arising out of the use
or non-use of these guidelines and the literature used in support of these guidelines.
3.5.5 Funding
The National Clinical Guideline Centre was commissioned by the National Institute for Health and
Care Excellence to undertake the work on this guideline.

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Osteoarthritis
Guideline summary
4 Guideline summary
4.1 Algorithms
4.1.1 Holistic assessment
Figure 2: Holistic assessment
Update 2014

38
Osteoarthritis
Guideline summary
Assessing needs: how to use this algorithm
This layout is intended as an aide memoire to provide a breakdown of key topics which are
commonly of concern when assessing people with osteoarthritis. Within each topic are a few
suggested specific points worth assessing. Not every topic will be of concern for everyone with
osteoarthritis, and there are other specifics which may warrant consideration for particular
individuals
4.1.2 Targeting treatment
Figure 3: Targeting treatment
oral NSAIDs
including COX-2
inhibitors opioids
capsaicin
intra-articular
corticosteroid
paracetamol injections
topical
NSAIDs
supports education, advice,
and braces information access
local heat and
cold
strengthening exercise
shock- aerobic fitness training
absorbing assistive
Update 2014
shoes or insoles weight loss if
devices
overweight/obese
TENS
manual therapy
(manipuation and joint
stretching) arthroplasty
Targeting treatment: how to use this algorithm
Starting at the centre and working outward, the treatments are arranged in the order in which they
should be considered for people with osteoarthritis, given that individual needs, risk factors and
preferences will modulate this approach. In accordance with the recommendations in the guideline,
there are three core interventions which should be considered for every person with osteoarthritis -
these are given in the central circle. Some of these may not be relevant, depending on the
individual,. for example, topical NSAIDs and capsaicin are suitable only for knee and hand
osteoarthritis.Where further treatment is required, consideration should be given to the second ring,
which contains relatively safe pharmaceutical options. Again, these should be considered in light of
the individual's needs and preferences. A third outer circle gives adjunctive treatments of less well-
proven efficacy, less symptom relief or increased risk to the patient. They are presented here in four
groups: pharmaceutical options, self-management techniques, surgery and other non-
pharmaceutical treatments.
NICE intends to undertake a full review of evidence on the pharmacological management of

osteoarthritis. This will start after a review by the MHRA of the safety of over-the-counter analgesics
is completed. In the meantime, the original recommendations (from 2008) remain current advice.

39
Osteoarthritis
Guideline summary
However, the GDG would like to draw attention to the findings of the evidence review on the
effectiveness of paracetamol that was presented in the consultation version of the guideline. That
review identified reduced effectiveness of paracetamol in the management of osteoarthritis
compared with what was previously thought. The GDG believes that this information should be taken
into account in routine prescribing practice until the intended full review of evidence on the
pharmacological management of osteoarthritis is published (see the NICE website for further details).
4.2 Key priorities for implementation

From the full set of recommendations, the GDG selected nine key priorities for implementation. The
criteria used for selecting these recommendations are listed in detail in The Guidelines Manual.327
The reasons that each of these recommendations was chosen are shown in the table linking the
evidence to the recommendation in the relevant chapter.
 Diagnose osteoarthritis clinically without investigations if a person:
o is 45 or over and
o has activity-related joint pain and
o has either no morning joint-related stiffness or morning stiffness that lasts no longer than
30 minutes. [new 2014]
 Offer advice on the following core treatments to all people with clinical osteoarthritis.
o Access to appropriate information (see recommendation 7).
o Activity and exercise (see recommendation 12).
o Interventions to achieve weight loss if the person is overweight or obese (see recommendation
14 and Obesity [NICE clinical guideline 43]). [2008, amended 2014]
 Offer accurate verbal and written information to all people with osteoarthritis to enhance
Update 2014
understanding of the condition and its management, and to counter misconceptions, such as that
it inevitably progresses and cannot be treated. Ensure that information sharing is an ongoing,
integral part of the management plan rather than a single event at time of presentation. [2008]
 Agree individualised self-management strategies with the person with osteoarthritis. Ensure that
positive behavioural changes, such as exercise, weight loss, use of suitable footwear and pacing,
are appropriately targeted. [2008]
 Advise people with osteoarthritis to exercise as a core treatment (see recommendation 6),
irrespective of age, comorbidity, pain severity or disability. Exercise should include:
o local muscle strengthening and
o general aerobic fitness.
It has not been specified whether exercise should be provided by the NHS or whether the healthcare
professional should provide advice and encouragement to the person to obtain and carry out the
intervention themselves. Exercise has been found to be beneficial but the clinician needs to make a
judgement in each case on how to effectively ensure participation. This will depend upon the
person's individual needs, circumstances and self-motivation, and the availability of local facilities.
[2008]
 Base decisions on referral thresholds on discussions between patient representatives, referring
clinicians and surgeons, rather than using scoring tools for prioritisation. [2008, amended 2014]
 Refer for consideration of joint surgery before there is prolonged and established functional
limitation and severe pain. [2008, amended 2014]
 Offer regular reviews to all people with symptomatic osteoarthritis. Agree the timing of the
reviews with the person (see also recommendation 42). Reviews should include:
o monitoring the person’s symptoms and the ongoing impact of the condition on their everyday
activities and quality of life
o monitoring the long-term course of the condition

40
Osteoarthritis
Guideline summary
o discussing the person’s knowledge of the condition, any concerns they have, their personal
preferences and their ability to access services
o reviewing the effectiveness and tolerability of all treatments
o support for self-management. [new 2014]
 Consider an annual review for any person with one or more of the following:
o troublesome joint pain
o more than one joint with symptoms
o more than one comorbidity
o taking regular medication for their osteoarthritis. [new 2014]
4.3 Full list of recommendations
1. Diagnose osteoarthritis clinically without investigations if a person:

 is 45 or over and
 has activity-related joint pain and
 has either no morning joint-related stiffness or morning stiffness that
lasts no longer than 30 minutes. [new 2014]
2. Be aware that atypical features, such as a history of trauma, prolonged
morning joint-related stiffness, rapid worsening of symptoms or the presence
of a hot swollen joint, may indicate alternative or additional diagnoses.
Important differential diagnoses include gout, other inflammatory arthritides
(for example, rheumatoid arthritis), septic arthritis and malignancy (bone
Update 2014
pain). [new 2014]
3. Assess the effect of osteoarthritis on the person’s function, quality of life,
occupation, mood, relationships and leisure activities. Use Figure 2 as an aid
to prompt questions that should be asked as part of the holistic assessment
of a person with osteoarthritis. [2008]
4. Take into account comorbidities that compound the effect of osteoarthritis
when formulating the management plan. [2008]
5. Discuss the risks and benefits of treatment options with the person, taking
into account comorbidities. Ensure that the information provided can be
understood. [2008]
6. Offer advice on the following core treatments to all people with clinical
osteoarthritis.
 Access to appropriate information (see recommendation 7).
 Activity and exercise (see recommendation 12).
 Interventions to achieve weight loss if the person is overweight or obese
(see recommendation 14 and Obesity [NICE clinical guideline 43]).
[2008, amended 2014]
7. Offer accurate verbal and written information to all people with
osteoarthritis to enhance understanding of the condition and its
management, and to counter misconceptions, such as that it inevitably
progresses and cannot be treated. Ensure that information sharing is an
ongoing, integral part of the management plan rather than a single event at
time of presentation. [2008]

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Osteoarthritis
Guideline summary
8. Agree a plan with the person (and their family members or carers as
appropriate) for managing their osteoarthritis. Apply the principles in Patient
experience in adult NHS services (NICE clinical guidance 138) in relation to
shared decision-making. [new 2014]
9. Agree individualised self-management strategies with the person with
osteoarthritis. Ensure that positive behavioural changes, such as exercise,
weight loss, use of suitable footwear and pacing, are appropriately targeted.
[2008]
10. Ensure that self-management programmes for people with osteoarthritis,
either individually or in groups, emphasise the recommended core
treatments (see recommendation 6), especially exercise. [2008]
11. The use of local heat or cold should be considered as an adjunct to core
treatments. [2008]
12. Advise people with osteoarthritis to exercise as a core treatment (see
recommendation 6), irrespective of age, comorbidity, pain severity or
disability. Exercise should include:
 local muscle strengthening and
 general aerobic fitness.
It has not been specified whether exercise should be provided by the NHS or
whether the healthcare professional should provide advice and
encouragement to the person to obtain and carry out the
intervention themselves. Exercise has been found to be beneficial but
Update 2014
the clinician needs to make a judgement in each case on how to
effectively ensure participation. This will depend upon the person's
individual needs, circumstances and self-motivation, and the
availability of local facilities. [2008]
13. Manipulation and stretching should be considered as an adjunct to core
treatments, particularly for osteoarthritis of the hip. [2008]
14. Offer interventions to achieve weight lossb as a core treatment (see
recommendation 6) for people who are obese or overweight. [2008]
15. Healthcare professionals should consider the use of transcutaneous electrical
nerve stimulation (TENS)c as an adjunct to core treatments for pain relief.
[2008]
16. Do not offer glucosamine or chondroitin products for the management of
osteoarthritis. [2014]
17. Do not offer acupuncture for the management of osteoarthritis. [2014]
18. Offer advice on appropriate footwear (including shock-absorbing properties)
as part of core treatments (see recommendation 6) for people with lower
limb osteoarthritis. [2008]
19. People with osteoarthritis who have biomechanical joint pain or instability
should be considered for assessment for bracing/joint supports/insoles as an
adjunct to their core treatments. [2008]
b
See Obesity: guidance on the prevention, identification, assessment and management of overweight and obesity in adults
and children (NICE clinical guideline 43).
c
TENS machines are generally loaned to the person by the NHS for a short period, and if effective the person is advised
where they can purchase their own.

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Osteoarthritis
Guideline summary
20. Assistive devices (for example, walking sticks and tap turners) should be
considered as adjuncts to core treatments for people with osteoarthritis who
have specific problems with activities of daily living. If needed, seek expert
advice in this context (for example, from occupational therapists or Disability
Equipment Assessment Centres). [2008]
21. Do not refer for arthroscopic lavage and debridementd as part of treatment
for osteoarthritis, unless the person has knee osteoarthritis with a clear
history of mechanical locking (as opposed to morning joint stiffness, 'giving
way' or X-ray evidence of loose bodies). [2008, amended 2014]
22. Healthcare professionals should consider offering paracetamol for pain relief
in addition to core treatments (see Figure 3 in section 4.1.2); regular dosing
may be required. Paracetamol and/or topical non-steroidal anti-
inflammatory drugs (NSAIDs) should be considered ahead of oral NSAIDs,
cyclo-oxygenase-2 (COX-2) inhibitors or opioids. [2008]
23. If paracetamol or topical NSAIDs are insufficient for pain relief for people
with osteoarthritis, then the addition of opioid analgesics should be
considered. Risks and benefits should be considered, particularly in older
people. [2008]
24. Consider NSAIDs for pain relief in addition to core treatments (see Figure 3
in section 4.1.2) for people with knee or hand osteoarthritis. Consider topical
NSAIDs and/or paracetamol ahead of oral NSAIDs, COX-2 inhibitors or
opioids. [2008]
25. Topical capsaicin should be considered as an adjunct to core treatments for
Update 2014
knee or hand osteoarthritis. [2008]
26. Do not offer rubefacients for treating osteoarthritis. [2008]
27. Where paracetamol or topical NSAIDs are ineffective for pain relief for
people with osteoarthritis, then substitution with an oral NSAID / COX-2
inhibitor should be considered. [2008]
28. Where paracetamol or topical NSAIDs provide insufficient pain relief for
people with osteoarthritis, then the addition of an oral NSAID / COX-2
inhibitor to paracetamol should be considered. [2008]
29. Use oral NSAIDs / COX-2 inhibitors at the lowest effective dose for the
shortest possible period of time. [2008]
30. When offering treatment with an oral NSAID / COX-2 inhibitor, the first
choice should be either a standard NSAID or a COX-2 inhibitor (other than
etoricoxib 60mg). In either case, co-prescribe with a proton pump inhibitor
(PPI), choosing the one with the lowest acquisition cost. [2008]
31. All oral NSAIDs / COX-2 inhibitors have analgesic effects of a similar
magnitude but vary in their potential gastrointestinal, liver and cardio-renal
toxicity; therefore, when choosing the agent and dose, take into account
individual patient risk factors, including age. When prescribing these drugs,
consideration should be given to appropriate assessment and/or ongoing
monitoring of these risk factors. [2008]
d
This recommendation is a refinement of the indication in Arthroscopic knee washout, with or without debridement, for
the treatment of osteoarthritis (NICE interventional procedure guidance 230). The clinical and cost-effectiveness
evidence for this procedure was reviewed for the original guideline (published in 2008), which led to this more specific
recommendation on the indication for which arthroscopic lavage and debridement is judged to be clinically and cost
effective.

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Osteoarthritis
Guideline summary
32. If a person with osteoarthritis needs to take low-dose aspirin, healthcare

professionals should consider other analgesics before substituting or adding
an NSAID or COX-2 inhibitor (with a PPI) if pain relief is ineffective or
insufficient. [2008]
33. Intra-articular corticosteroid injections should be considered as an adjunct to
core treatments for the relief of moderate to severe pain in people with
34. Do not offer intra-articular hyaluronan injections for the management of
35. Clinicians with responsibility for referring a person with osteoarthritis for
consideration of joint surgery should ensure that the person has been
offered at least the core (non-surgical) treatment options (see
recommendation 6 and Figure 3 in section 4.1.2). [2008]
36. Base decisions on referral thresholds on discussions between patient
representatives, referring clinicians and surgeons, rather than using scoring
tools for prioritisation. [2008, amended 2014]
37. Consider referral for joint surgery for people with osteoarthritis who
experience joint symptoms (pain, stiffness and reduced function) that have a
substantial impact on their quality of life and are refractory to non-surgical
treatment. [2008, amended 2014]
38. Refer for consideration of joint surgery before there is prolonged and
established functional limitation and severe pain. [2008, amended 2014]
Update 2014
39. Patient-specific factors (including age, sex, smoking, obesity and
comorbidities) should not be barriers to referral for joint surgery. [2008,
amended 2014]
40. When discussing the possibility of joint surgery, check that the person has
been offered at least the core treatments for osteoarthritis (see
recommendation 6 and Figure 3 in section 4.1.2), and give them information
about:
 the benefits and risks of surgery and the potential consequences of not
having surgery
 recovery and rehabilitation after surgery
 how having a prosthesis might affect them
 how care pathways are organised in their local area. [new 2014]
41. Offer regular reviews to all people with symptomatic osteoarthritis. Agree
the timing of the reviews with the person (see also recommendation 42).
Reviews should include:
 monitoring the person’s symptoms and the ongoing impact of the
condition on their everyday activities and quality of life
 monitoring the long-term course of the condition
 discussing the person’s knowledge of the condition, any concerns they
have, their personal preferences and their ability to access services
 reviewing the effectiveness and tolerability of all treatments
 support for self-management. [new 2014]
42. Consider an annual review for any person with one or more of the following:

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Guideline summary
 troublesome joint pain

 more than one joint with symptoms
 more than one comorbidity
 taking regular medication for their osteoarthritis. [new 2014]
43. Apply the principles in Patient experience in adult NHS services (NICE clinical
guidance 138) with regard to an individualised approach to healthcare
services and patient views and preferences. [new 2014]
4.4 Key research recommendations
Update 2014
1. What are the short-term and long-term benefits of non-pharmacological and pharmacological
treatments for osteoarthritis in very old people (for example, aged 80 years and older)?
2. What are the benefits of combinations of treatments for osteoarthritis, and how can these be
included in clinically useful, cost-effective algorithms for long-term care?
3. What are effective treatments for people with osteoarthritis who have common but poorly
researched problems, such as pain in more than one joint or foot osteoarthritis?
4. Which biomechanical interventions (such as footwear, insoles, braces and splints) are most
beneficial in the management of osteoarthritis, and in which subgroups of people with
osteoarthritis do they have the greatest benefit?
5. In people with osteoarthritis, are there treatments that can modify joint structure, resulting in
delayed structural progression and improved outcomes?

45
Osteoarthritis
Diagnosis
5 Diagnosis
5.1 Introduction
In CG59 (2008) the GDG considered the following to represent a clinician’s working diagnosis of
peripheral joint osteoarthritis:
 persistent joint pain that is worse with use
 age 45 years old and over
 morning stiffness lasting no more than half an hour.
This working diagnosis is very similar to the American College of Rheumatologists’ clinical diagnostic
criteria for osteoarthritis of the knee that were designed to differentiate between an inflammatory
arthritis such as rheumatoid arthritis and osteoarthritis (Altman et al. 1986).
No disagreement with this working definition was raised at consultation or publication on the last
guideline or in the public consultation on the update review undertaken prior to the commissioning
of this update. As this definition is in line with other international definitions, the GDG have chosen
not to undertake a review on the diagnostic accuracy of this working diagnosis. However, the GDG
have clarified the criteria to avoid ambiguity. The revised wording is that osteoarthritis should be
diagnosed clinically without investigations if a person:
Update 2014
 has no morning joint-related stiffness, or morning stiffness that lasts no longer than 30 minutes.
The GDG generally felt that patients meeting their working diagnosis of osteoarthritis did not
normally require radiological investigations but considered it important to review the available
evidence in this area to identify whether there was any additional benefit to imaging patients as part
of the diagnostic pathway. The clinical guideline update scope required the GDG to assess the role of
imaging as part of the clinical diagnosis. The GDG considered it important to reassure clinicians that
by not undertaking routine imaging in patients with a clinical diagnosis of osteoarthritis, no signs and
symptoms (red flags) or serious underlying pathologies would be missed. The GDG therefore pre-
specified potential signs and symptoms and underlying pathologies that they felt that missing would
be of concern to clinicians and undertook a review to identify how many serious pathologies/red flag
symptoms had been identified in imaging studies of osteoarthritis.
Other symptoms and examination findings that the GDG considered add to diagnostic certainty are
discussed in Section 5.1.5, Recommendations and link to evidence.
The working diagnosis of osteoarthritis excludes the following joint disorders which are not
addressed in these guidelines: inflammatory arthritis (including rheumatoid and psoriatic arthritis,
ankylosing spondylitis, gout and reactive arthritis) and connective tissue disorder with associated
arthritides. However, it is important to recognise that many patients with inflammatory arthritis have
secondary osteoarthritis and that these guidelines could also apply to these patients.

46
Osteoarthritis
Diagnosis
5.1.1 In a person with suspected clinical OA (including knee pain) when would the addition of
imaging be indicated to confirm additional or alternative diagnoses (particularly to identify
red flags) such as:
-Crystal arthritis (gout or CPPD)
-Inflammatory arthritis (including rheumatoid arthritis, psoriatic arthritis)
-Infection
-Cancer, usually secondary metastases?
The GDG identified signs and symptoms in a patient with suspected OA that might indicate other
serious underlying pathology. The presence of these signs or symptoms (“red flags”) may warrant
further investigation or referral (see table 8 for details).
The GDG reviewed the literature about the use of imaging patients with signs or symptoms of other
serious underlying pathology in patients with suspected OA.
The red flags identified by the GDG are listed in the table below.
Table 8: Red flags for further investigation or referral

Red flags in history that may indicate further Red flags on clinical examination that may indicate
investigation or referral further investigation or referral
Update 2014
Progressive, well-localised pain that does not vary Pattern of joints affected
with activity, posture or time of day Redness, calor, Swelling, Tenderness, Deformity
Pain worse at rest (Calor, dolor, rubor, and tumor: Heat, pain, redness,
Pain significantly worse at night and swelling.)
Prolonged morning stiffness > 2 hours Significant loss of range of movement or locked joint
Unexplained mass or swelling
Presence of co-morbid conditions that are
Weakness, wasting, numbness, loss of reflexes or
associated with inflammatory arthritis eg psoriasis,
hyperreflexia
inflammatory bowel disease, diarrhoeal infections,
Loss of peripheral pulses
STIs
Skin rashes
Presence of history or exam features suggesting
Temporal artery tenderness
connective tissue disease
Pain not reproduced by usual movement during
Persistent marked effusion(s) examination (cancer)
Recurrent fevers Instability of joint (soft tissue trauma)
Multiple joints affected Lymphadenopathy
Family history of arthritis Systemically unwell (fever, jaundice, sepsis)
Gradual onset before age 40
Past history of psoriasis, inflammatory bowel
disease, diarrhoeal infections (Salmonella, Shigella or
Campylobacter), iritis and uveitis, conjunctivitis,
Reiter’s disease, urethral discharge, cervicitis,
(Chlamydia trachomatis or Neisseria gonorrheae),
enthesitis, sacroiliitis
Skin rashes
Night sweats
Unplanned weight loss
True locking
Paraesthesiae, numbness,
Weakness (e.g. shoulder and pelvic girdle weakness
and pain – Polymyalgia Rheumatica)
Vascular or spinal claudicant pain (including jaw)

47
Osteoarthritis
Diagnosis
Red flags in history that may indicate further Red flags on clinical examination that may indicate
investigation or referral further investigation or referral
Transient visual loss (Temporal arteritis)
History of trauma
Histobreast, kidney, thyroid, prostate)
HIV
Intravenous drug abuse
Immunosuppression (drugs or disease)
Chronic cough
Contact with TB
Thoracic pain
Constant pain unrelated to movement, exercise or
posture, particularly at night (cancer)
Sphincter disturbance and perianal loss of sensation
Occupational exposure to chemicals or trauma
Table 9: Possible serious underlying pathologies
Infection
Cancer
Fracture
Crystal arthropathy
Soft Tissue Trauma and Peri-articular Disorders
Inflammatory Disorders
Vascular Disorders (e.g. claudicant pain)
Update 2014
Neurological Disorders (e.g. radiculopathy or neuropathic pain)
Referred pain from adjacent joints and structures
For full details see review protocol in Appendix C.
Table 10: PICO characteristics of review question

Review Question In a person with suspected clinical OA (including knee pain) when would the
addition of imaging be indicated to confirm additional or alternative
diagnoses (particularly to identify red flags) such as:
 Crystal arthritis (gout or CPPD)
 Inflammatory arthritis (including rheumatoid arthritis, psoriatic arthritis)
 Infection
 Cancer, usually secondary metastases
Population Adults with a suspected diagnosis of OA (including knee pain)
Intervention/s  X-ray
 MRI
 Ultrasound
 CT
 Scintigraphy
Comparison/s  Clinical diagnosis + imaging
 Clinical diagnosis alone

48
Osteoarthritis
Diagnosis
Outcomes
Endpoints will be reported as per study.
 Sensitivity
 Specificity
 Likelihood ratio
 Diagnostic accuracy
 Other clinical management outcomes (e.g. referral)
Study design  Systematic reviews and meta-analyses

 RCTs
 Observational studies
5.1.2 Clinical evidence

This evidence review has been structured in two parts:
Part 1 will aim to look at the use of imaging in the diagnosis of OA compared to clinical diagnosis. The
main focus is to explore the correlation or agreement between imaging (e.g. x-ray) and clinical
diagnosis.
Update 2014
Part 2 aims to look at the prevalence/ incidence of abnormalities detected by imaging people with
OA or joint pain. So, for example, a study may be using x-rays on people with OA and has reported
the incidence of different abnormalities, which are potentially warning signs or signs of serious
underlying pathologies.
Evidence from these are summarised in the clinical GRADE evidence profile below. See also the study
selection flow chart in Appendix D, forest plots in Appendix I, study evidence tables in Appendix G
and exclusion list in Appendix J.
5.1.2.1 Part 1: The use of imaging in the diagnosis of OA compared to clinical diagnosis
Seven studies were included in this part of the review209,236,240,245,246,358,406: Two systematic reviews
compared radiographic diagnostic criteria to clinical diagnostic criteria240,406; one systematic review
236
and two studies published after the systematic review 209,246 compared ultrasound (US)
assessment to clinical diagnostic criteria, and two studies assessed the use of MRI in diagnosis
compared to clinical examination 245,358. The studies included in this review are summarised in table
11.
Table 11: Summary of studies included in the review (part 1)

Intervention/
Study comparison Population Outcomes Comments
Radiological vs clinical diagnostic criteria
Schiphof 2008 Radiography vs People with or Sensitivity and Only 2 studies
Clinical without knee OA specificity of included in this SR
examination (18 studies radiological vs reported on the
included) clinical assessment interventions of
and clinical vs interest
clinical+radiographi

49
Osteoarthritis
Diagnosis
Intervention/
c
Kinds 2011 Radiography vs People with hip or Agreement/ no Assessed quality of
Clinical knee OA (45 agreement/ studies
examination publications inconsistent
reporting on 39 between
studies) radiographic and
clinical exam
Ultrasound vs clinical diagnostic criteria
Keen 2009 Ultrasound vs People with OA of Agreement/ no Population
clinical knee, hip, foot, agreement/ included people
examination and hand, SI joint (47 inconsistent with OA at sites
symptoms studies included) between US and excluded in
clinical exam protocol.
Koutroumpas 2010 Ultrasound/ power People with hand % agreement
doppler vs clinical OA (n=15) between US/ power
examination Doppler and clinical
examination for
inflammation and
tenderness
Iagnocco 2010 All patients -outpatients with Significant Cross-sectional
underwent clinical chronic, painful correlation study
exam and knee OA (n=82) between clinical
Ultrasound of both and US findings
Update 2014
knees
MRI vs clinical diagnostic criteria
Kornaat 2006 All patients - People diagnosed Association Prospective cohort
completed a with OA and their between clinical (part of Genetics,
questionnaire and siblings (n=210; and MRI findings OA and
underwent MRI 105 sibling pairs) progression study)
- At baseline n=71
diagnosed with
clinical OA and
n=97 diagnosed
with radiographic
OA
Petron 2010 All patients People (aged >40 Change in diagnosis Retrospective
underwent MRI years) with MRI of OA/ cohort
(44/100 had scans (n=100) degenerative joint - study assessed
radiographs, 24/44 disease pre and change in diagnosis
had a weight post MRI by pre and post MRI
bearing x-ray) primary care or
study physician
Radiography versus clinical +/- radiographic examination
Schiphof presented the sensitivity and specificity of radiographic vs clinical and radiographic vs
radiographic+clinical criteria; the details are presented in clinical evidence tables (appendix G). Two
studies included in Schiphof (2008) matched our protocol 142,256
LaValley (2001) assessed the sensitivity and specificity of three different clinical assessment
methods/ instruments and radiographic assessment compared to radiographic assessment alone.

50
Osteoarthritis
Diagnosis
The radiographic criteria used in the study were: Kellgren and Lawrence score ≥ grade 2 for
tibiofemoral compartment, or ≥ grade 2osteophyte or ≥ grade 2 JSN and ≥ grade 1 osteophyte for
patellofemoral compartment and positive answer to the question “do you have pain on most days in
either knee?”
The clinical assessment instruments used were:

 Sensitive instrument: screening questions (1) pain or discomfort when walking ¼ mile and
Screening question (2) how long does the stiffness take to wear off? And screening question (3)
have you had knee pain on more than 2 occasions in the last year?
 Specific instrument: Exam and screening question (1) pain or discomfort when walking ¼ mile and
screening question 2 “has a Dr ever told you you have arthritis in your knees?”
 Efficient instrument: Screening question (1) pain or discomfort when walking ¼ mile
The sensitivity and specificity ranged from 46.2% to 84.2% and 72.8 to 94.1% respectively, and the
positive and negative likelihood ratios ranged from 3.1 to 7.83 and 0.28 to 0.57 respectively for
clinical assessment + radiographic criteria vs radiographic assessment alone.
The study by Felson (1997) compared radiographic criteria vs radiographic + clinical criteria. The
clinical criteria (reported in Schiphof 2008) were knee symptoms and crepitus on physical
examination. The different radiographic+ clinical criteria were:
 Kellgren-Lawrence score ≥2
 Alternate radiographic definition 1: Osteophytes ≥ grade 2 or Joint Space Narrowing (JSN) ≥ grade
2 (grade 0-3) with either sclerosis, cysts or grade 1 osteophyte
 Alternate radiographic definition 2: same as alternate definition 1 or osteophytes grade 1 and any
sclerosis or JSN
Update 2014
 Alternate radiographic definition 3: same as alternate definition 1 or sum of individual
radiographic features ≥ grade 2
The sensitivity and specificity ranged from 59.1% to 77.4% and 37.1% to 76.6%, and the positive and
negative likelihood ratios ranged from 1.23 to 2.53 and 0.53 to 0.67 respectively for radiographic
criteria vs radiographic + clinical criteria.
Kinds (2011)240 reported that out of 39 studies, 4 (10%) reported agreement between clinical and
radiological criteria for diagnosing hip and knee OA, 7 (18%) reported no agreement between clinical
and radiological criteria for diagnosing hip and knee OA and 28 (72%) reported inconsistent
agreement between clinical and radiological criteria for diagnosing hip and knee OA
Ultrasound (US) versus clinical examination
The results from the systematic review from Keen (2009) are presented in Table 12.
Table 13: Results from Keen (2009)236: agreement of US compared to clinical diagnosis
Pathology imaged US vs clinical assessment US vs symptoms
Cartilage N=2 studies N=1 study
- 1 study showed - Results stated as N/A
agreement
Tendon and ligament N=3 studies -
- 1 study showed US
better that clinical
assessment
- 1 study there was no
pathology found
- 1 study showed US not

51
Osteoarthritis
Diagnosis
Pathology imaged US vs clinical assessment US vs symptoms

as good as clinical
assessment
Cortical N=1 study -
- No correlation between
US and clinical
assessment
Synovial abnormalities N=10 studies N= 8 studies
- 7 studies showed - 5 studies showed agreement
agreement between US between US and symptoms
and clinical assessment - 1 study showed no agreement
- 2 studies showed no between US and symptoms
correlation - 2 studies did not report results
- -1 study reported
results as N/A
(a) <Insert Note here>
Keen (2009)236 noted that there was no consistent relationship between clinical symptoms and US
detected pathology. They also stated that there were several limitations to the data:
 The definition of OA was not consistent and was not reported in 50% of the studies included
in the review
 There was a lack of definition of pathology and imaging appearance.
Of the two studies published after the systematic review, one reported that there was a statistically
Update 2014
significant correlation between total ultrasound score and both VAS and Lequesne index scores209.
The other study reported the percentage (%) agreement between US or power Doppler and clinical
examination: For US compared to clinical exam there was 72.7% agreement for detecting
inflammation and 62.6% agreement for detecting tenderness, for Power Doppler vs clinical exam
there was 74.1% agreement for detecting inflammation and 65.3% agreement for detecting
tenderness246
MRI versus clinical examination
Of the two studies reporting MRI vs clinical examination, one study358 reported the diagnoses made
by the referring physician and the study physician before and after MRI, results are presented in
Table 14.
Table 15: Number of diagnoses of OA/ degenerative joint disease before and after MRI (Petron
2010)
(a) (a)
Physician making diagnosis Pre MRI diagnosis Post MRI diagnosis
Primary care (individuals own 6/100 40/100
physician)
Orthopaedic specialist (study 28/100 37/100
physician)
(a) Number of diagnoses out of 100 participants included in the study
Kornaat (2006)245 reported the association between clinical assessment and MRI findings (see Forest
plot in Appendix I). There was no clear or consistent association between clinical assessment and MRI
assessment in detecting any abnormality except a grade 2 or 3 effusion.

52
Diagnosis
Osteoarthritis
Table 16: Modified GRADE table for the use of imaging (radiography, ultrasound, MRI) compared to clinical assessment in the diagnosis of OA
Study characteristics Quality Assessment Summary of findings
Number Design No. of Limitation Inconsistency* Indirectness Imprecision* Other Outcomes Quality
of studies in consideration
studies review/
number of
patients
Radiography vs clinical assessment: Schiphof 2008, Kinds 2011

2 Systematic N=18 studies Serious N/A No serious N/A - LaValley (2001) Clinical vs clinical + MODERATE
240,406 1
review in Schiphof limitations indirectness radiographic
(2008); n= 39 Sensitive instrument:
studies in Sensitivity: 84.2 %
Kinds (2011) Specificity: 72.8%
LR+: 3.1, LR-:0.28
PPV: 30.5 NPV: NR
Update 2014
Specific instrument
Sensitivity: 46.2%
53
Specificity: 94.1%
LR+: 7.83, LR-: 0.57
PPV: 52.1, NPV: NR
Efficient instrument
Sensitivity: 56.6%
Specificity: 85.1%
LR+: 3.8, LR-: 0.51
PPV: 34.7, NPV: NR
Felson (1997)
Radiographic vs clinical
K-L:
Sensitivity: 59.1%
Specificity: 76.6%
LR+: 2.53, LR-: 0.53
PPV: NR, NPV: NR
Alternate 1:
Sensitivity: 61.3%
Specificity: 69.6%
LR+: 2.02, LR-: 0.56
PPV: NR, NPV: NR
Diagnosis
Osteoarthritis
studies review/
number of
patients
Alternate2:
Sensitivity: 68.1%
Specificity: 47.8%
LR+: 1.30, LR-: 0.67
PPV: NR, NPV: NR
Alternate 3:
Sensitivity: 77.4%
Specificity: 37.1%
LR+: 1.23, LR-: 0.61
PPV: NR, NPV: NR
Update 2014
Kinds (2011)
Agreement: 4/39
No agreement: 7/39
54
Inconsistent: 28/39
Ultrasound/ Power doppler vs clinical assessment or symptoms: Keen 2009, Koutroumpas 2010, Iagnocco 2010
3 Systematic N=47 studies Serious N/A No serious N/A - Keen (2009) MODERATE
236 2
review in Keen limitations indirectness Cartilage pathology:
and (2009); 1/2 studies agree
prospective N=18 in Tendon and ligament pathology:
209,246
cohort Koutroumpas 1/3 studies agree, 1/3 studies had no results,
(2010); n=82 1/3 studies had no agreement
in Iagnocco Cortical pathology:
(2010) 1 study, no agreement
Synovial pathology:
7/10 studies show agreement, 2/10 no
agreement and 1/10 NR
Koutroumpas (2010)
US
Inflammation: 72.7%
Tenderness: 62.6%
Power Doppler
Inflammation: 74.1%
Diagnosis
Osteoarthritis
studies review/
number of
patients
Tenderness: 65.3%
Iagnocco (2010)
Statistically significant agreement between US
score and VAS and US and Lequesne index
MRI vs clinical assessment: Petron 2010, Kornaat 2006
2 Prospective N=310 Serious N/A Serious N/A - Petron (2010) LOW
245 3 3
cohort limitations indirectness Primary care physician
Update 2014
and Pre MRI: 6%
retrospective Post MRI: 40%
358
cohort Study physician
55
Pre-MRI: 28%
Post MRI: 37%
Kornaat (2006) (OR [95%CI])
Cartilaginous defects:
1.12 (0.40, 3.14)
Osteophytes:
1.05 (0.338, 2.90)
Subchondral cysts:
1.71 (0.81, 3.61)
Bone marrow oedema:
1.36 (0.65, 2.85)
Meniscal tears:
1.26 (0.58, 2.74)
Subluxation of meniscus:
1.03 (0.48, 2.21)
Effusion grade 2 or 3:
9.99 (1.13, 88.31)
Bakers cysts:
1.68 (0.80, 3.53)
1
Diagnosis
Osteoarthritis
Kinds (2011) reports results as agreement, no agreement or inconsistent. The strength of association is not reported as estimates and comparisons differ between studies and are not clearly
described. Schiphof (2008) includes 18 studies, but only 2 studies report interventions of relevance to the review protocol. The aim of the review is slightly different from the aim of this
review; it was focussed on the comparison of different classification systems for OA.
Update 2014
2
Keen (2009) study quality is reported in a separate appendix. Only two databases were searched (Pubmed and Medline). The review contained studies with comparisons not of relevance to
our protocol; therefore not all of the 39 studies included in the review are included in our analysis. Koutroumpas (2010) is a small study (n=18).
3
Kornaat (2010) included people with spinal OA (an excluded population in the protocol), and was a study primarily focussed on genetics of OA which recruited sibling pairs. Petron (2010)
included people who had undergone MRI on their knees; the population did not have to have OA or knee pain.
4
Alternate 1 diagnostic criteria included: Osteophytes ≥ grade 2 or Joint Space Narrowing (JSN) ≥ grade 2 (grade 0-3) with either sclerosis, cysts or grade 1 osteophyte
5
Alternate 2 diagnostic criteria included: same as alternate definition 1 or osteophytes grade 1 and any sclerosis or JSN
6
Alternate 3 diagnostic criteria included: same as alternate definition 1 or sum of individual radiographic features ≥ grade 2
*could not be assessed as data was not meta-analysed
56
Osteoarthritis
Diagnosis
5.1.2.2 Part 2: The frequency of abnormalities detected by imaging people with OA or joint pain
35,65,105,129,183,209,245,294,308,358
Ten studies were included in this part of the review , one study was only available in
308
abstract form . Data on the incidence of the abnormalities found on imaging have been extracted from the
ten studies included in this review and are presented in Table 17 .
The studies included in the review were heterogeneous with regards to study design, population, intervention
and outcomes reported:
Table 18: Summary of studies included in the review (part 2)

Intervention/
35
Bierma 2002 All patients People >50 years Bursitis Prospective
underwent clinical, with hip pain Neurological cohort
laboratory and (n=220) disorder
radiological
examination
65
Chan 1991 All patients People with clinical Subchondral cysts Prospective trial-
underwent MRI, CT, and radiological Meniscal Part of a clinical
X-ray evidence of knee abnormalities drug trial on
OA (n=20) Iigamentous effects of NSAIDs
changes on OA
-only assessed 1
knee in each
Update 2014
patient (most
severe knee used
in people with
bilateral OA)
105
De Miguel 2006 All people Population divided Suprapatellar Cross sectional
underwent clinical into 2 groups: effusion study
radiographic and Group A- people Meniscal lesion
ultrasound with knee pain Baker’s cyst
examination. during physical
Infrapatellar
activity (n=81) and
bursitis
Group B- people
without knee pain Anserine
(n=20) tendinobursitis
129
Duer 2008 All patients had People with RA Prospective
previously unclassified Other inflammatory cohort-
undergone clinical, arthritis despite diseases (Diagnoses before
biochemical and conventional Arthralgias without and after
radiological exam. clinical, biochemical inflammatory or intervention)
All patients and radiological degenerative origin
underwent MRI of examination (n=41)
the most
symptomatic hand
and MCP and whole
body bone
scintigraphy
183
Hayes 2005 All patients N=117 women, Subchondral cysts Prospective
underwent clinical classified into Joint effusion cohort (Southeast

57
Osteoarthritis
Diagnosis
Intervention/
assessment and X- groups +/- pain and Meniscal Michigan OA
ray; patients had +/- OA abnormalities cohort)
MRI 1 year after
radiography
209
Iagnocco 2010 All patients -outpatients with Baker’s cysts Cross-sectional
underwent clinical chronic, painful Cartilage study
exam and knee OA (n=82) abnormalities
Ultrasound of both
knees
245
Kornaat 2006 All patients - People diagnosed Subchondral cysts Prospective
completed a with OA and their Joint effusion cohort (part of
questionnaire and siblings (n=210, 105 Meniscal Genetics, OA and
underwent MRI sibling pairs) abnormalities progression
study)
- At baseline n=71
diagnosed with
clinical OA and
n=97 diagnosed
Update 2014
with radiographic
OA
294
McCrae 1992 All patients People thought to Sclerosis Cross-sectional
underwent clinical have OA in one or Subchondral cysts study
exam, x-ray and both knees (n=100) - included people
bone scintigraphy with possible
secondary OA
(n=17)
308
Micallef 2010 All patients had the People with bone Fractures Retrospective
Widespread Bone and joint pain Inflammatory review (Abstract
and Joint Pain (WP) (n=77) arthritis only)
Bone Scan Protocol Metastases/
(included Blood osteomyelytis
pool images, static
images of the hands
and feet, SPECT/CT
of required region)
358
Petron 2010 All patients People (aged >40 Meniscus injury Retrospective
underwent MRI years) with MRI Ligament injury cohort
(44/100 had scans (n=100) OA/ degenerative - study assessed
radiographs, 24/44 joint disease change in
had a weight diagnosis pre and
bearing x-ray) post MRI

58
Diagnosis
Osteoarthritis
Table 19: Results summary: abnormalities identified by imaging

2
Study ID Bierma Chan 1991 De Miguel Duer 2008 Hayes Iagnocco Kornaat McCrae 1992 Micallef Petron
1, 4 1, 2 1 6 1
2002 2006 2005 2011 2006 2010 2010
2, 3
Key study -Hip pain -people with - people +/- -Hands, -Women -People with -people -People -people -people
details -clinical clinical and knee pain (2 wrists and +/- pain chronic, diagnosed thought to with bone >40 years
5
(joint assessed, exam radiological groups ) feet and +/- painful knee with OA and have OA in and joint who had
imaging and x-ray evidence of -Clinical exam, -clinica l OA OA their siblings one or both pain undergone
modality) OA x-ray, and US exam, x- (divided -clinical exam - knees -Blood pool an MRI
-x-ray, CT, ray, MRI into 4 and US Questionnair -clinical exam, images, scan
MRI and bone groups) e and MRI x-ray and static -MRI (only
scintigraph -clinical bone images of 44/100 had
y exam and scintigraphy hands and previously
x-ray, feet, undergone
MRI 1 SPECT/CT of x-ray)
Update 2014
year after required
59
x-ray region
Abnormalities identified on imaging
Baker’s cysts Group A 12/232 5/164 (3%) 96/205
(pain): (5.2%) (46.8%)
30/81 (37%)
Group B (no
pain):
3/20 (15%)
RA/ RA: Inflammato
inflammatory 13/41 ry arthritis:
arthritis (31.7%) 7/77 (9.1%)
Other
inflammator
y disease:
11/41
(26.8%)
Diagnosis
Osteoarthritis
2
1, 4 1, 2 1 6 1
2002 2006 2005 2011 2006 2010 2010
2, 3
Bursitis Trochant Infrapatellar

eric bursitis:
bursitis Group A:
or 7/81 (8.6%)
tensoniti Group B: 0
s:
Anserine
22/220 tendinobursi
(10%) tis:
Group A:
5/81 (6.2%)
Group B: 0
Update 2014
Neurological 5/220
disorder (2.3%)
60
Subchondral Grade 3 89/205 M: 6/200

cysts changes (43.4%) (3%)
Radiography: L:6/200 (3%)
M:0/20 PF: 25/200
L: 0/20 (12.5%)
PF: 0/20
CT:
M: 0/20
L: 0/20
PF: 0/20
MRI:
M: 0/20
L: 0/20
PF: 0/20
Effusion Suprapatella 6/232 Synovial Grade 2 or
r effusion: (2.6%) effusion: 3:
Diagnosis
Osteoarthritis
2
1, 4 1, 2 1 6 1
2002 2006 2005 2011 2006 2010 2010
2, 3
Group A: 60/164(36.6 15/205

64/81 (79%) %) (7.3%)
Group B:
7/20 (35%)
Cartilage 124/164
abnormalities
Meniscal Grade 3 Meniscal Meniscal Primary
abnormalities/ changes lesion: tears: care
injury medial Group A: 138/205 Pre MRI:
meniscus: 37/81 (67.3%) 24/100
Anterior : (45.7%) Subluxation (24%)
Update 2014
16/20 (80%) Group B: of meniscus: Post-MRI:
Posterior : 8/20 (40%) 74/205 23/100
19/20 (95%) (36.1%) (23%)
61
Lateral Orthopaedi
meniscus: c specialist
10/20 (50%) Pre MRI:
Posterior of 23/100
lateral (23%)
meniscus: Post-MRI:
15/20 (75%) 24/100
(24%)
Ligament Complete MCL or Pre
abnormalities/ tears LCL: MRI:12/10
injury ACL and PCL: Grade 3 0 (12%)
8/20 (40%) sprain: Post-MRI:
0/232 18/100
ACL or (18%)
PCL: Orthopaedi
Edema c specialist
Diagnosis
Osteoarthritis
2
1, 4 1, 2 1 6 1
2002 2006 2005 2011 2006 2010 2010
2, 3
or Pre MRI:
sprain: 8/100 (8%)
5/232 Post-MRI:
(2.2%) 7/100 (7%)
Complet
e tear:
2/232
(0.86%)
Sclerosis Radiography: (subchondral)
2/20 (10%) M: 55/200
CT: (22.5%)
1/20 (5%) L:30/200
Update 2014
MRI: (15%)
3/20 (15%) PF: 41/200
62
(20.5%)
Synovitis 3/232
(1.3%)
Bone marrow Grade 2 or
Oedema 3:
36/205
(17.6%)
Internal Primary
derangement care
Pre MRI:
19/100
(19%)
Post-MRI: -
Orthopaedi
c specialist
Pre MRI:0
Diagnosis
Osteoarthritis
2
1, 4 1, 2 1 6 1
2002 2006 2005 2011 2006 2010 2010
2, 3
Post-MRI:0
OA/ 53/77 Primary
degenerative (68.8%) care
changes Pre MRI:
6/100 (6%)
Post-MRI:
40/100
(40%)
Orthopaedi
c specialist
Update 2014
Pre MRI:
28/100
(28%)
Post-MRI:
63
37/100
(37%)
Fractures 6/77 (7.8%)
Bony 0/77
metastases
Osteomyelitis 0/77
*Abbreviations: M= medial; L= Lateral; PF= patellofemoral
1
values are number of people
2
values are number of joints
3
values are knees with moderate o r large structure/ finding
4
30/220 people unknown or missing
5
RCT: group A- with knee pain on activity, Group B- patients without knee pain for 1 month prior to inclusion
6
Abstract only
Diagnosis
Osteoarthritis
Table 20: Modified GRADE table for the use of imaging in the differential diagnosis of OA

Number Design No. of Limitation Inconsistency* Indirectness Imprecision* Other Number of Quality
of patients consideration abnormalities
studies detected with
imaging
Baker’s cyst: De Miguel 2006, Hayes 2005, Iagnocco 2010, Kornaat 2006
1 2
4 Prospective 510 Serious N/A Serious N/A - 146/702 (20.8%) LOW
183,245
cohort & [range 3 to 46.8%)
cross-sectional
105,209
RA/ inflammatory arthritis: Duer 2008, Micallef 2010

4
2 Prospective cohort 118 Very N/A Serious N/A - RA: 31.7% VERY LOW
129 4, 8
and serious Inflammatory
retrospective cohort arthritis: 15.7%
Update 2014
308
[range 9.1 to
26.8%)
64
Bursitis: Bierma-Zeinstra 2002, De Miguel 2006

1, 10 1
2 Prospective cohort 321 Serious N/A Serious N/A - Trochanteric LOW
35
and cross bursitis: 10%
105
sectional Infrapatellar
bursitis: 8.6%
Anserine
tendinobursitis:
6.2%
Neurological disorder: Bierma-Zeinstra 2002
10
1 Prospective cohort 220 Serious N/A No serious N/A - 2.3% MODERATE
35
indirectness
Subchondral cysts: Chan, 1991, Kornaat 2006, McCrae 1992
6
3 Prospective cohort 330 Very N/A Serious N/A - 29.6% VERY LOW
65,245 3, 6,
and cross serious
294 7
sectional
Effusion (including suprapatellar, synovial effusion and grade 2 or 3 effusion): De Miguel 2006, Hayes 2005;Iagnocco 2010, Kornaat 2006
1, 2, 1,
4 Cross sectional 510 Serious N/A Very serious N/A - 21.7% [range 2.6 to VERY LOW
105,209 5, 6 2, 6
and 79%]
prospective cohort
183,245
Diagnosis
Osteoarthritis
imaging
Cartilage abnormalities: Iagnocco 2010

209 5
1 Cross sectional 82 Serious N/A No serious N/A - 75.6% MODERATE
indirectness
Meniscal abnormalities/ injury (including meniscal lesions, tears and subluxation): Chan 1991, De Miguel 2006, Kornaat 2006, Petron 2010
105 1,
4 Cross sectional , 330 Very N/A Very serious N/A - 70% [range 23 to VERY LOW
1, 6, 6, 9
prospective cohort serious 95%]
65,245 9
and
retrospective cohort
358
Ligament abnormalities/ injury (including MCl or LCL grade 3 sprain, ACL or PCL oedema or sprain or complete tear): Chan 1991, Hayes 2005, Petron 2010
Update 2014
2, 9 2, 9
3 Prospective cohort 217 Serious N/A Serious N/A - 9.4% [range 0.86 to LOW
65,183
and 40%)
65
retrospective cohort
358
Sclerosis (medial, lateral and patellofemoral): Chan 1991, McCrae 1992

2 Prospective cohort 120 Very N/A No serious N/A - X-ray: 58.2% [range LOW
65 3, 7
and cross serious indirectness 10 to 63%]
294
sectional CT: 5%
MRI: 15%
Synovitis: Hayes 2005
2 2
1 Prospective cohort 117 Serious N/A Serious N/A - 1.3% LOW
183
Bone marrow oedema: Kornaat 2006

6
1 Prospective cohort 210 Very N/A Very serious N/A - 17.6% VERY LOW
245 6
serious
Internal derangement: Petron 2010
9 9
1 Retrospective 100 Serious N/A Serious N/A - - LOW
358
cohort
OA/ degenerative changes: Micallef 2010, Petron 2010
8,
2 Retrospective 177 Very N/A Very serious N/A - 41.2% VERY LOW
308,358 8, 9 9
cohort serious
Fractures: Micallef 2010
Diagnosis
Osteoarthritis
imaging
8
1 Retrospective 77 Very N/A Serious N/A - 7.8% VERY LOW
308 8
cohort serious
Bony metastases: Micallef 2010
8
1 Retrospective 77 Very N/A Serious N/A - - VERY LOW
308 8
cohort serious
Update 2014
Osteomyelitis: Micallef 2010
8
1 Retrospective 77 Very N/A Serious N/A - VERY LOW
308 8
cohort serious
*could not be assessed as data was not meta-analysed

1
The study by DeMiguel (2006) was a small study divided into two groups with unbalanced demographic. The study excluded people with septic, inflammatory and crystal arthritis.
2
Hayes (2005) had four groups, with or without pain and with or without OA. The results for all groups have been pooled and therefore may be skewed .Additionally; participants only
66
underwent MRI 1 year after radiography.

3
Chan (1991) was a very small study (n=20), and the sensitivity of radiography may be overestimated.
4
Duer (2008) does not specify what “other inflammatory disease” included
5
Iagnocco (2010) excluded those participants with evidence of other rheumatic disease.
6
Kornaat (2006) included people with multisite OA, including spinal OA, and was part of a larger study on genetics of OA, siblings were recruited into the study
7
McCrae (1992) excluded people with evidence of inflammatory arthropathies. 17 people had evidence of secondary OA.
8
Micallef (2010) was only available as a published abstract only and provides limited detail about the study. The protocol for imaging is not well defined.
9
Petron (2010) was a retrospective review of people who had undergone MRI, not only people with knee pain or OA . The study focussed on the diagnosis of OA before and after an MRI. For
the purposes of this review, the post MRI results for primary care providers have been use
10
Bierma (2002) had 13.6% of data missing and with no recorded diagnosis
Osteoarthritis
Diagnosis
5.1.3 Economic evidence
Published literature
No relevant economic evaluations comparing imaging with a clinical diagnosis alone/clinical diagnosis
plus imaging were identified.
Unit costs
In the absence of recent UK cost-effectiveness analysis, relevant unit costs are provided below to aid
consideration of cost effectiveness.
Table 21: Imaging costs

Imaging procedure Cost HRG code and description
X-ray £29 DAPF

Direct Access Plain Film
MRI £163 RA01Z
Magnetic Resonance Imaging Scan, one area, no contrast
Ultrasound £53 RA23Z
Ultrasound Scan less than 20 minutes
CT £95 RA08Z
Computerised Tomography Scan, one area, no contrast
Update 2014
Scintigraphy £181 RA36Z
Nuclear Medicine - category 2
111
(a) Outpatient costs from the NHS reference costs 2009-10
5.1.4 Evidence statements
Clinical
Part 1 review
 Two systematic reviews reported on the use of radiographic imaging+/- clinical assessment vs
clinical assessment in the diagnosis of OA .
o One study included in the systematic review reported that using clinical + radiological
diagnostic criteria (reference test) compared to radiological diagnosis alone resulted in a range
of sensitivities and specificities of 46.2-84.2% and 72.8-94.1% respectively and a range of
positive and negative likelihood ratios of 3.1-7.86 and 0.28 – 0.57 respectively.
o Another study included in the systematic review that compared radiographic vs clinical
diagnosis criteria (reference test) resulted in a range of sensitivities and specificities of 59.1-
77.4% and 37.1- 76.6% respectively, and a range of positive and negative likelihood ratios of
1.23- 2.53 and 0.53- 0.67 respectively.
o A further systematic review reported that there was agreement between radiological and
clinical diagnosis in 4/39 studies, there was no agreement between radiological and clinical
diagnosis in 7/39 studies and there was inconsistent agreement between radiological and
clinical diagnosis in 28/39 studies
 One systematic review, which included 47 studies, suggested that there was no consistent
agreement between US imaging (of cartilage, tendon and ligament, cortical or synovial structures)
and clinical diagnosis of OA. One small study (n=18) reported that the percentage agreement
between US and clinical diagnosis was 72.7% for inflammation and 62.6% for tenderness, and the

67
Osteoarthritis
Diagnosis
percentage agreement between Power Doppler and clinical diagnosis was 74.1% for inflammation
and 65.3% for tenderness. A second study (n=82) reported that there was statistically significant
agreement between both the US score, the VAS pain score and the Lequesne index score.
 Two studies (n=310) suggested that there was inconsistent agreement between MRI and clinical
diagnosis of OA
Part 2 review
 Four studies (n=510) showed that the incidence of Baker’s cysts detected with imaging (MRI, CT,
US or x-ray) was 20.8%, with a range of 3 to 46.8% [LOW QUALITY].
 One study (n= 41) showed that the incidence of Rheumatoid Arthritis detected with imaging (MRI
and bone scintigraphy) was 31.7%; Two studies (n=118) showed that the incidence of
inflammatory arthritis was 15.7%, with a range of 9.1 to 26.8% [VERY LOW QUALITY].
 One study (n=220) showed that the incidence of trochanteric bursitis or tendonitis detected with
imaging (x-ray) was 10%; one study (n=101) showed that the incidence of infrapatellar bursistis
and anserine tendinobursitis detected with imaging (ultrasound) was 8.6% and 6.2% respectively
[LOW QUALITY].
 One study (n=220) showed that the incidence of neurological disorder detected with imaging (x-
ray) was 2.3% [MODERATE QUALITY].
 Three studies (n=330) showed that the incidence of subchondral cysts detected with x-ray was
18.6%; the incidence detected with CT was 45% and the incidence detected with MRI was 45.3%
[VERY LOW QUALITY].
 Four studies (n= 510) showed that the incidence of effusion (including suprapatellar, synovial
effusion and Grade 2 or 3 effusion) detected with imaging (x-ray, US or MRI) was 21.7%, with a
Update 2014
range of 2.6 to 79% [VERY LOW QUALITY].
 One study (n=82) showed that the incidence of cartilage abnormalities detected with ultrasound
imaging was 75.6% [MODERATE QUALITY].
 Four studies (n=330) showed that the incidence of meniscal abnormalities or injury (including
meniscal lesion, tears and subluxation) detected with imaging (US and MRI) was 70%, with a
range of 23 to 95% [VERY LOW QUALITY].
 Three studies (n=217) showed that the incidence of ligament abnormalities or injury (including
MCL or LCL grade 3 sprain, ACL or PCL oedema or sprain or complete tear) detected with MRI was
79.4%, with a range of 0.86 to 40% [LOW QUALITY].
 Two studies (n=120) showed that the incidence of sclerosis (medial , lateral and patellofemoral)
detected with x-ray was 58.2% (range 10 to 63%), the incidence detected with CT was 5% and the
incidence detected with MRI was 15% [LOW QUALITY].
 One study (n=117) showed that the incidence of synovitis detected with MRI was 1.3% [LOW
QUALITY].
 One study (n=210) showed that the incidence of bone marrow oedema (grade 2 or 3) detected
with MRI was 17.6% % [VERY LOW QUALITY].
 One study (n=100) showed that no incidences of internal derangement were detected with MRI
[LOWQUALITY].
 Two studies (n=177) showed that the incidence of OA or degenerative changes detected with
imaging (MRI and a protocol that included static imaging and SPECT/CT) was 41.2%, with a range
of 40 to 68.8% [VERY LOW QUALITY].
 One study (n=77) showed that the incidence of fractures detected with an imaging protocol that
included static imaging and SPECT/CT was 7.8% % [VERY LOW QUALITY].
 One study (n=77) showed that the no incidences of bony metastases were detected with an
imaging protocol that included static imaging and SPECT/CT [VERY LOW QUALITY].

68
Osteoarthritis
Diagnosis
 One study (n=77) showed that the no incidences of osteomyelitis were detected with an imaging
protocol that included static imaging and SPECT/CT [VERY LOW QUALITY].
Economic
 No relevant economic evaluations were identified.
5.1.5 Recommendations and link to evidence

1. Diagnose osteoarthritis clinically without investigations if a person:
 has either no morning joint-related stiffness or morning stiffness that
lasts no longer than 30 minutes. [new 2014]
2. Be aware that atypical features, such as a history of trauma, prolonged

morning joint-related stiffness, rapid worsening of symptoms or the
presence of a hot swollen joint, may indicate alternative or additional
diagnoses. Important differential diagnoses include gout, other
inflammatory arthritides (for example, rheumatoid arthritis), septic
Recommendations arthritis and malignancy (bone pain). [new 2014]
Relative values of The GDG considered that the critical outcomes for decision-making were
different sensitivity, specificity and incidence/prevalence of abnormalities.
Update 2014
outcomes Associations/correlations between clinical and radiological findings were also
considered important to decision-making.
Trade off between The GDG considered that people presenting to health professionals with
clinical benefits osteoarthritis complain of joint pain, not of radiological change. The GDG
and harms recognised that many of the studies reviewed will have only included
participants with symptomatic radiological osteoarthritis and that they are
inferring any positive or negative treatment effects apply equally to those
with or without radiological change.
The GDG felt that patients meeting the working diagnosis of osteoarthritis as
stated in the above recommendation do not normally require radiological or
laboratory investigations. This working diagnosis is very similar to the
American College of Rheumatologists’ clinical diagnostic criteria for
osteoarthritis of the knee that were designed to differentiate between an
inflammatory arthritis such as rheumatoid arthritis and osteoarthritis
Part 1 of this review looked at the correlation of radiographic,

ultrasonograpghic and MRI diagnosis compared to a clinical assessment, and
found no consistent agreement between imaging modalities and clinical
diagnosis.
Radiography
Two systematic reviews assessing the use of radiographic imaging +/- clinical
assessment reported that using clinical + radiological diagnostic criteria
compared to radiological diagnosis alone resulted in a wide range of
sensitivities and specificities of 46.2-84.2% and 72.8-94.1% respectively and a
range of positive and negative likelihood ratios of 3.1-7.86 and 0.28 – 0.57
respectively.

69
Osteoarthritis
Diagnosis
Ultrasonography
One systematic review which included 47 studies suggested that there was
no consistent agreement between US imaging (of cartilage, tendon and
ligament, cortical or synovial structures) and clinical diagnosis of OA
MRI
Two studies suggested that there was inconsistent agreement between MRI
and clinical diagnosis of OA
Part 2 of this review attempted to identify the frequency of abnormalities

other than OA detected by imaging people with OA, suspected OA or joint
pain. Within the ten studies identified, a variety of additional or alternative
diagnoses were identified including trochanteric bursitis, rheumatoid
arthritis and neurological disorders. The GDG felt that most of the evidence
was of very low quality and that incidences quoted were too wide ranging to
recommend any imaging modality to routinely detect alternative
abnormalities.
Economic The costs of the various diagnostic imaging techniques can vary from £29 (x-
considerations ray) to almost £200 depending on the type of imaging.
The GDG felt that a clinical diagnosis is sufficient to diagnose OA and

additional imaging procedures would increase costs with no significant
Update 2014
benefits.
Where imaging may be helpful is to confirm a differential diagnosis.
Whether the addition of imaging is cost effective depends upon the

sensitivity and specificity of the imaging techniques in diagnosing OA, and
also upon the prevalence of the disease. In other words, the prior probability
of someone having OA affects how certain you are that someone has OA
when a scan indicates OA. Thus, if a clinical diagnosis is sufficient to indicate
OA, then those patients for whom the clinician is not sure of the diagnosis
and sends for imaging, are probably not very likely to have OA, and is
incurring costs by confirming a likely diagnosis that could have been made
clinically.
There is utility associated with a correct diagnosis, and also disutility

associated with an incorrect diagnosis. Imaging would be helpful if a
differential diagnosis is being considered, and where the pre-test prevalence
is not very rare. Thus this patient will experience disutility if they are
diagnosed as having OA when actually it is something else, and they are
missing out on treatment, which they could be benefitting from, as well as
disutility from this incorrect prognosis and delayed diagnosis of the actual
problem.
The GDG experts advised that more MRI scans are being done than
necessary, especially in those over the age of 45. This is a concern in terms of
resource use because more imaging is being done without being sure of the
diagnosis. The GDG felt that this should be addressed because the evidence
shows that the sensitivity and specificity of imaging for unsuspected
diagnoses is not high enough to use imaging where no clinical diagnosis has
been made.

70
Osteoarthritis
Diagnosis
Quality of Part 1 of this review looked at the correlation of radiographic,

evidence ultrasonograpghic and MRI diagnosis compared to a clinical assessment, and
found no consistent agreement between imaging modalities and clinical
diagnosis. The quality of this evidence from systematic reviews ranged from
moderate to low.
Part 2 of this review attempted to identify the prevalence or incidence of

abnormalities other than OA detected by imaging people with OA, suspected
OA or joint pain. Within the ten studies identified a variety of additional or
alternative diagnoses were identified including trochanteric bursitis,
rheumatoid arthritis and neurological disorders, and may not be relevant
clinically. The GDG felt that the incidence rates quoted were wide ranging
and the vast majority of the evidence was of too low quality to recommend
any imaging modality to routinely detect alternative abnormalities.
Other Other symptoms and examination findings that the GDG considered that add
considerations to diagnostic certainty include:
 Inactivity pain and stiffness, known as "gelling". This is very common, for
example after prolonged sitting, and should be distinguished from locking,
which is a feature normally associated with prevention of limb
straightening during gait, and suggests meniscal pathology
 Examination findings of crepitus or bony swelling
 Radiological evidence of osteoarthritis (joint space loss, osteophyte
Update 2014
formation, subchondral bone thickening or cyst formation)
 Absence of clinical or laboratory evidence of inflammation such acutely
inflamed joints or markers of inflammation (raised erythrocyte
sedimentation rate, C-reactive protein or plasma viscosity).
However, the GDG commented that additional tests should only be

considered where there is an unusual presentation or an alternative
diagnosis is being considered.
The GDG identified a number of atypical features that might raise concern
and a number of differential diagnoses that clinicians should be aware of
when considering making a diagnosis of OA and chose to make a
recommendation in this regard to inform an appropriate diagnosis. They did
not recommend any subsequent diagnostic or treatment strategies as these
would not be relevant to this guideline.
With reference to recommendation 1, as outlined in the introduction to this

chapter, the GDG advised that the use of the working diagnosis used in CG59
should be formalised into a recommendation for the purposes of this update.
They noted that this definition is in line with other international definitions
and chose not to undertake a review on the diagnostic accuracy of this
working diagnosis. They asserted a thorough clinical history and appropriate
examination were the most important features of an assessment to make a
positive diagnosis of osteoarthritis and, from the evidence presented, the
addition of investigations did not provide benefit over and above the clinical
diagnosis.

71
Osteoarthritis
Holistic approach to osteoarthritis assessment and management
6 Holistic approach to osteoarthritis assessment

and management
6.1 Principles of good osteoarthritis care
People with osteoarthritis may experience a number of challenges to their lives as a consequence of
their symptoms. Some of these challenges have an effect on the individual’s ability to contribute to
society or enjoy a reasonable quality of life. A holistic approach to care considers the global needs of
an individual, taking into account social and psychological factors that have an effect on their quality
of life and the ability to carry out activities of daily living, employment related activities, family
commitments and hobbies 395.
A holistic assessment of the individual’s medical, social and psychological needs can enable a tailored
approach to treatment options encouraging positive health seeking behaviours that are relevant to
the individual’s goals. A therapeutic relationship based on shared decision making endorse the
individual ability to self-manage their conditions and reduce the reliance on pharmacological
therapies providing a greater sense of empowerment for the individual 87,422.
These principles should also encompass a patient centred approach to communication providing and
a mutual goal sharing approach that encourages a positive approach to rehabilitation 431.
6.1.1 Recommendations
3. Assess the effect of osteoarthritis on the person’s function, quality of life, occupation, mood,
relationships and leisure activities. Use Figure 1 as an aid to prompt questions that should be
asked as part of the holistic assessment of a person with osteoarthritis. [2008]
4. Take into account comorbidities that compound the effect of osteoarthritis when formulating
the management plan. [2008]
5. Discuss the risks and benefits of treatment options with the person, taking into account
comorbidities. Ensure that the information provided can be understood. [2008]
6. Offer advice on the following core treatments to all people with clinical osteoarthritis.
 Access to appropriate information (see recommendation 7).
 Activity and exercise (see recommendation 12).
 Interventions to achieve weight loss if the person is overweight or obese (see
recommendation 14 and Obesity [NICE clinical guideline 43]). [2008, amended 2014]
See sections 4.1.1 and 4.1.2 for the associated algorithms.
6.2 Patient experience and perceptions

6.2.1 Clinical introduction
This guideline provides practitioners with evidence-based recommendations on treatments for
people with osteoarthritis. The guidance on specific treatments is necessary but not sufficient for the
provision of effective, high quality health care. Other information is required. This includes the
physical, psychological and social assessment of the patient, and the effect that joint pain or joint
dysfunction has on their life. The skills of good history taking and clinical examination of the

72
Osteoarthritis
locomotor system are crucial as is the knowledge of when to request further investigations and the
interpretation of these tests. Effective communication skills allow the practitioner to fully understand
the context of osteoarthritis in their patient’s life and to provide the patient with an accurate
assessment, explanation and prognosis. Management options, benefits and risks can be shared with
the patient to allow an informed decision to be made. A good knowledge of the context of
musculoskeletal healthcare provision and expertise in the locality as well as good communication
with the providers of health and social care are also necessary.
6.2.2 Methodological introduction

We looked for studies that investigated patient experiences of osteoarthritis and its treatments and
how patient perceptions influence their preference and outcome for treatments. Due to the large
volume of evidence, studies were excluded if they used a mixed arthritis population of which <75%
had osteoarthritis or if population was not relevant to the UK.
One cohort study163 and 18 observational studies21,45,86,126,143,174,175,188,251,254,378,380,398,438,440,461,475,484

were found on patient experiences of osteoarthritis and its treatments. One of these studies126 was
excluded due to methodological limitations.
The cohort study assessed the experiences of N=90 patients, comparing those with osteoarthritis
with non-osteoarthritis patients.
The 17 included observational studies were all methodologically sound and differed with respect to:
study design (N=11 observational-correlation; N=3 qualitative; N=1 observational; N=1 case-series)
and trial size.

All evidence statements in this section are level 3.
6.2.3.1 Body function and structure (Symptoms)
Ten studies86,143,163,174,175,251,398,440,461,475.
Observational and qualitative studies found that pain, function and negative feelings were important
factors affecting the lives of patients with OA. Patients found their pain was distressing and that their
OA caused limitations and had a major impact on their daily life. The areas that caused major
problems for patients were: pain, stiffness, fatigue, disability, depression, anxiety and sleep
disturbance.
6.2.3.2 Activities and participation
Nine studies45,86,163,254,378,380,398,440,475.
Observational and qualitative studies found that poor performance of tasks was associated with
female gender, BMI, pain and pessimism. Patients often felt embarrassed at not being able to do
things that their peers could do and one of the things they felt most distressing was not being able to
do activities that they used to be able to do. The most frequent activities affected by osteoarthritis
were: leisure activities, social activities, close relationships, community mobility, employment and
heavy housework. Personal care activities were rarely mentioned. OA also impacted employment
status. Both middle-aged and older-age adults described the loss of valuable roles and leisure
activities such as travel, and were less likely to mention employment. Loss of these activities was
described as extremely upsetting.

73
Osteoarthritis
Pre-task self-efficacy beliefs and knee pain was found to influence the speed of movement, post-task
difficulty ratings and perceptions of physical ability. Work ability did not differ with gender, however
patients with hip OA had the worst work ability scores and in non-retired patients white-collar
workers had significantly higher work ability than blue-collar workers, regardless of age.
6.2.3.3 Psychosocial and personal factors: feeling old
Two studies163,398
Observational and qualitative studies found that many patients viewed their OA symptoms as an
inevitable part of getting old, that their older age had rendered their disabilities ‘invisible’ and they
were not viewed as being legitimately disabled because they were old (i.e. disability should be
expected and accepted in old age). Many also felt that there were negative stereotypes of older age
and that they were a burden on society and wanted to distance themselves from such stereotypes.
Patients often minimised or normalised their condition (which was more commonly done among
older patients who attributed it to age).
6.2.3.4 Psychosocial and personal factors: depression, anxiety, life satisfaction
Eleven studies21,45,86,143,163,174,175,251,254,438,440
Observational and qualitative studies found that pessimism was correlated with all physical outcome
measures. More joint involvement was associated with negative feelings about treatment and with
negative mood. Being female was associated with less impact of osteoarthritis on AIMS2 Affective
Status and stressed women reported greater use of emotion-focused coping strategies, felt their
health was under external control, perceived less social support and were less satisfied with their
lives. Greater perceived social support was related to higher internal health locus of control. Patients
expressed that their aspirations for future life satisfaction had declined appreciably and that
depression and anxiety were major problems that they experienced. Older patients with advanced
OA felt that the disease threatened their self-identities and they were overwhelmed by health and
activity changes and felt powerless to change their situation. Many ignored their disease and tried to
carry on as normal despite experiencing exacerbated symptoms.
Patients were unable to guarantee relief from symptoms based on lifestyle changes alone and this
was linked to upset feelings, helplessness and depression. Many expressed frustration, anxiety and
fear about the future. Pain was correlated with greater depression and lower life satisfaction
whereas support and optimism were correlated with fewer depressive symptoms and greater life
satisfaction.
In non-retired patients, white-collar workers had worse mental status than blue-collar workers.
Those with hip OA also had the worst mental status. Those with worse mental status had lower work
ability. Mental health was worse for persons with OA compared with those not suffering from OA.
6.2.3.5 Psychosocial and personal factors: relationships
Three studies21,163,174
Observational and qualitative studies found that in OA patients, symptoms affected mood and made
them frustrated and annoyed with others. Informal social networks (family, friends and neighbours)
were critical to patients management and coping, particularly marital relationships and the decision
not to have joint replacement surgery, since networks helped with tasks, gave emotional support and
helped keep patients socially involved and connected to others despite their physical limitations,
reinforcing the idea that surgery is avoidable. Decisions were made on ability of marital couple's
ability to cope rather than individual’s capacity and thus health professionals may need to consider
the couple as the patient when considering disease management options.

74
Osteoarthritis
6.2.3.6 Psychosocial and personal factors: knowledge of arthritis and its management
Six studies21,174,188,251,398,475
Observational and qualitative studies found that most patients expected to have OA permanently
and did not believe that a cure for OA was likely or that there was no effective way of treating OA
and this they were reluctant to seek treatment for their OA. Beliefs about the cause and control of
OA and the helpfulness of treatment showed no relationship to general health perceptions. Patients
were predominantly externally controlled in terms of their health beliefs (believe their health is the
result of fate or another’s actions). Most patients thought their OA was a ‘normal’ and ‘integral’ part
of their life history, was an inevitable result of hardship or hard work (common view amongst men
and women and across different occupational groups). Some felt that younger people might be more
‘deserving’ of treatment than themselves. Younger respondents did not perceive their symptoms as
being normal, this affected their approach to management and their determination to get formal
treatment.
Many patients were unsure as to the causes and physiology of OA, were uncertain how to manage an
acute episode and unclear as to the likely ‘end point’ of the disease (ending up in a wheelchair). The
most frequently cited causes were: accidents/injuries, occupational factors, cold or damp weather,
too much acid in the joints, old age, weight and climatic factors. Many patients knew about NSAIDs
and steroid injections but did not always know about their side-effects and some thought that taking
their drug therapy regularly would reducing the progression of their OA. Many also knew about the
benefits of exercise and weight loss but did not know suitable forms of exercise. Many did not know
about the benefits of lifestyle changes or using aids and devices. Arthritis was perceived as
debilitating but was not the primary health concern in participants’ lives.
6.2.3.7 Psychosocial and personal factors: expectations desired from treatment
Three studies174,398,475
Observational and qualitative studies found that most patients felt it was ‘very’ or ‘extremely’
important to try to prevent their OA from getting worse. Areas where patients most wanted
improvements were in pain management, mobility/functional ability and maintaining an
independent life in the community. Pain was a major concern for most patients, however their main
goals were to maximise and increase their daily activity as a strategy to manage their pain, rather
than identifying ‘pain control’ itself as a major or single issue.
6.2.3.8 Psychosocial and personal factors: use of self-management methods
Five studies174,175,398,438,440
Observational and qualitative studies found that patients with more education were more likely to
use active pain coping methods. The more serious and symptomatic that participants perceived their
condition to be, the less positive they felt about the management methods they used to control it).
Patients reporting use of alcohol (compared to never using alcohol) reported less control over good
and bad days. Use of self-management methods was associated with symptoms and seriousness but
not with age or gender. A number of patients felt embarrassed about their disabilities and felt stigma
in using walking aids or wheelchairs – some disguised their needs for using walking aids. Frequent
use of problem-focused coping strategies was associated with greater perceived social support.
Alternative therapies (e.g. ginger, cod-liver oil, acupuncture, magnets and others) were frequently
used by many of the patients. Some felt they were helpful and others thought benefits were due to
placebo effects. Despite lack of evidence for complementary therapies and dismissal from the
medical profession, patients were prepared to try anything that others had found helpful. Patients
wanted more information about the condition, self-help and available treatment options. Coping

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strategies used by patients included carrying on regardless, taking medication as required, exercise,
use of aids to daily living, restricting movement and resting.
6.2.3.9 Psychosocial and personal factors: treatment / healthcare
Seven studies21,163,174,398,440,475
Observational and qualitative studies found that most patients found at least one aspect of their
treatment made them feel better, no aspect of their treatment made them feel worse, perceived
helpfulness of treatment was inversely related to negative feelings about treatment. Older patients
and women were more likely to rate their treatment as more helpful. Patients with higher
occupational status were more likely to feel more negatively about their treatment. Employed
younger respondents had all paid for private referrals to specialists and had all undergone or were
being considered for total joint replacement surgery. Drugs were seen as helpful, surgery was
perceived as the only way to ‘cure’ the disease (but some avoided it due to fear of risks or felt they
were too old to benefit). Canes were perceived as useful but some felt embarrassed and did not use
them. Physiotherapy and regular exercise were seen as beneficial treatments. Most patients were
satisfied with their treatment and felt there was little more their GP could do for them.
Treatments most used by patients were: very often (tablets, aids and adaptations, physical therapy)
and treatments most patients had not tried were injections, removal of fluid/debris, aids and
adaptations, physical therapy, complementary therapy, education and advice, no treatment and
knee replacement. Treatments found moderately helpful by patients were tablets and top
treatments found extremely helpful were tablets, physical therapy, aids and adaptations and removal
of fluid/debris. The top treatment found not helpful was physical therapy. Treatments that patients
felt should be made priority for researchers were knee replacement, pain relief, cure, reduced
swelling, education and advice and physical therapy.
Many were unwilling to use medication and obtained information on activities and foods that were
perceived as harmful. Treating pain with medication for these people was seen as masking rather
than curing symptoms and was seen as potentially harmful due to increased risk of unwanted side-
effects. Long delays between experiencing symptoms and an osteoarthritis diagnosis made OA
symptoms more difficult to deal with. Younger respondents attributed this delay to health
professionals not considering OA as a possibility because participants were ‘too young’ to have
arthritis. Barriers receiving support noted mainly by younger OA patients were the ‘invisibility’ of
symptoms and their unpredictable nature. Others often exhorted them to engage in activities when
they were in pain, were disappointed when plans were unexpectedly cancelled or were suspicious
about the inability of participants to engage in some activities.
Patients felt that they there was a real lack of information and support given to them (from their GP
and other primary care team member) about their condition, especially in the areas of managing pain
and coping with daily activities. Many felt difficulties in communicating with doctors and some were
extremely dissatisfied with the service they had received. Many patients reported that their
doctor/health professional ignored their symptoms and had re-enforced the view that their OA was
normal for their age and patients were aware that they could be considered a burden on the NHS.
Obtaining information and more visits to the doctor was associated with reporting more symptoms
and with believing treatment to be more helpful.
Common problems reported by patients were: Inadequate supply of medications to last until their
next GP appointment, GI problems, barriers to attending clinic (e.g. finances, transportation) and
problems requiring rapid intervention. Women were significantly more likely to have inadequate
supply of medication and GI complaints were more prevalent among persons who were Caucasian,
younger and non-compliant. Persons with worse AIMS ratings or with poorer psychological health
were more likely to have reported barriers to care.

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Some participants mentioned that previous non-arthritis related surgical experiences (their own or
others) created fear and mistrust of surgery that contributed to the avoidance of TJA. Some noted
that previous experience with physicians, particularly around prescribing medications, had
undermined their trust in their physicians and often left them believing that their interests came
second. Several noted that their family physician had never discussed surgery with them and because
they were regarded as experts in treatment, participants assumed that surgery was not possible and
was also not a viable option and were given the impression that surgery was something to be
avoided. Where surgery had been mentioned by health professionals, it was often described as a last
resort, leaving many participants wanting to try all other alternatives before TJA.
6.2.4 From evidence to recommendations
Assessment of the individual
Every patient brings their thoughts, health beliefs, experiences, concerns and expectations to the
consultation. It is important to acknowledge distress and assess current ability to cope. Exploring the
background to distress is fruitful as psychosocial factors are often more closely associated with
health status, quality of life and functional status than measures of disease severity (such as X-
rays).395,422 Identifying psychosocial barriers to recovery and rehabilitation is important in a subgroup
of patients.
There is evidence to show that patients’ perception of how patient centred a consultation is strongly
predicts positive health outcomes and health resource efficiency (i.e. fewer referrals and
investigations).431
The GDG considered that there were three key areas to include in patient-centred assessment:
1)Employment and social activities
There is an association with osteoarthritis and certain occupations (e.g. farmers and hip
osteoarthritis, footballers with a history of knee injuries and knee osteoarthritis). Health and
employment are closely intertwined and conversely unemployment can be associated with ill health
and depression. Patients with osteoarthritis can have difficult choices to make with regard to
continuing in work, returning to work after time away, changing the nature of their work, or deciding
to stop working. Practitioners provide sickness certification and therefore often have to give
guidance, discuss work options and know sources of further help, both in the short term and the long
term. The Disability Discrimination Act (DDA) 1995 makes it unlawful for employers to treat a
disabled person less favourably than anyone else because of their disability, in terms of recruitment,
training, promotion and dismissal. It also requires employers to make reasonable adjustments to
working practices or premises to overcome substantial disadvantage caused by disability. Reasonable
adjustments can include, where possible: changing or modifying tasks; altering work patterns; special
equipment; time off to attend appointments; or help with travel to work. Advice about workplace
adjustments can be made by physiotherapists, occupational therapists or an occupational health
department if available. There are government schemes and initiatives available to help patients if
they wish to start, return or continue working:
http://www.direct.gov.uk/en/DisabledPeople/Employmentsupport/index.htm
2)Comorbidity
Osteoarthritis is more common in older age groups and therefore it is more likely that other
conditions will coexist. This raises several issues:
 A patient’s ability to adhere with exercise, for example if angina, COPD, previous stroke or obesity
are present.

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Osteoarthritis
 Polypharmacy issues. The choice of drug treatments for osteoarthritis as outlined in this guidance
can be influenced by the drugs taken for other conditions, for example patients who are taking
warfarin should not take NSAIDs, and may find that other analgesics alter the levels of
anticoagulation.
 Other medical conditions can influence the choice of treatments for osteoarthritis, such as a
history of duodenal ulcer, chronic kidney impairment, heart failure, liver problems.
 The risk of falls increases with polypharmacy, increasing age, osteoarthritis and other medical
conditions.
 The presence of severe comorbid conditions may influence the decision to perform joint
replacement surgery.
 Prognosis of osteoarthritis disability is worse in the presence of 2 or more comorbidities.
 Quality of sleep can be adversely affected by osteoarthritis and other co-morbid conditions.
 Depression can accompany any chronic and long term condition. The CG23 Depression: NICE
guideline recommends that screening should be undertaken in primary care and general hospital
settings for depression in high-risk groups – for example, those with significant physical illnesses
causing disability.
3)Support network
Carers provide help and support. They also need support themselves. It is important to be aware of
the health beliefs of carers and to respect their ideas, concerns and expectations as well as those of
the patient. Advice is available for support for carers both nationally (direct.gov.uk) and locally via
social services. Some patients have no social support and risk becoming isolated if their osteoarthritis
is progressive. Good communication between primary care and social services is essential in this
scenario.
Clinical assessment
The evidence base given in other parts of this guideline tends to assess interventions in terms of
patient reported outcomes. The working diagnosis of osteoarthritis is a clinical one based on
symptoms and therefore when considering which treatment options to discuss with the patient, it is
also important accurately to assess and examine the locomotor system. There are several points to
consider:
 It is important to assess function. For example, assessment of the lower limb should always
include an assessment of gait. (See footwear section, aids and devices for evidence base).
 The joints above and below the effected joint should be examined. Sometimes pain can be
referred to a more distal joint, for example hip pathology can cause knee pain.
 An assessment should be made as to whether the joint pain is related to that region only,
whether other joints are involved, or whether there is evidence of a widespread pain disorder.
 It is worth looking for other treatable periarticular sources of pain such as bursitis, trigger finger,
ganglions, very localised ligament pain, etc, which could respond quickly to appropriate
treatment. (see analgesic sections for evidence base).
 An assessment should be made of the severity of joint pain and/or dysfunction to decide whether
early referral to an orthopaedic surgeon is required. There is evidence that delaying joint
replacement until after disability is well established reduces the likelihood of benefit from
surgery. (see referral to surgery section for evidence base).

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Pain assessment
Pain is the most common presentation of osteoarthritis. It can be episodic, activity related, or
constant. It can disturb sleep. Analgesics are readily available over the counter, or prescribed, or
sometimes borrowed from others. It is important to know how the analgesics are being taken –
regularly or “as required”, or both as well as timing, dose frequency and different drugs being used.
Attitude to taking painkillers, side effects (experienced or anticipated) are all relevant in
understanding the impact of painful joints for the patient as well as providing valuable information
for a management plan. Disturbed sleep can lead to the loss of restorative sleep which in turn can
cause daytime fatigue, deconditioning of muscles and muscle pain similar to that found in chronic
widespread pain syndromes. Some patients can progress to developing chronic pain which is now
known to be maintained by several pathophysiological mechanisms which currently can be dealt with
only partially.
Patient-centred decision making
In order to achieve a holistic approach to care patients must be encouraged to consider a range of
factors that can enhance their self management approaches to coping with their condition.113,241
Self-management requires a "toolbox" approach of core treatments and adjuncts which can be tried
if required. The patient is then able to deal with exacerbations confidently and quickly.
It is worth considering what part of the osteoarthritis journey the patient is on. In the early stages
there is joint pain and uncertain diagnosis, later on symptomatic flares, with possible periods of
quiescence of varying length. In one longitudinal study in primary care over 7 years,355 25% of
patients with symptomatic osteoarthritis improved. Some people have rapidly progressive
osteoarthritis; others have progressive osteoarthritis which may benefit from surgery. Some patients
will opt for and benefit from long term palliation of their symptoms. As a rough guide, osteoarthritis
of the hip joint can progress to requiring joint replacement fairly quickly over the first few years,
osteoarthritis of the knee joint often has a slower progression over five to ten years, and nodal hand
osteoarthritis can have a good prognosis, at least in terms of pain. Within these generalizations there
can be substantial variation.
To effectively deliver these evidence based guidelines a holistic approach to the needs of the patient
needs to be made by the practitioner. One focus of this should be the promotion of their health and
general wellbeing. An important task of the practitioner is to reduce risk factors for osteoarthritis by
promoting self care and empowering the patient to make behavioural changes to their lifestyle. To
increase the likelihood of success, any changes need to be relevant to that person, and to be specific
with achievable, measurable goals in both the short and the long term. Devising and sharing the
management plan with the patient in partnership, including offering management options, allows for
the patient’s personality, family, daily life, economic circumstances, physical surroundings and social
context to be taken into account. This patient centred approach not only increases patient
satisfaction but also adherence with the treatment plan. Rehabilitation and palliation of symptoms
often requires coordination of care with other health care professionals and other agencies such as
social services. The GMC publication “Good Medical Practice”161 encourages practitioners to share
with patients, in a way they can understand, the information they want or need to know about their
condition, its likely progression, and the treatment options available to them, including associated
risks and uncertainties. This is particularly relevant when discussing surgical options or using drugs
such as NSAIDs. Risk is best presented to patients in several ways at once: for example as absolute
risk, as relative risk and as “number needed to harm”.
These guidelines give many different options for the management of a patient who has
osteoarthritis. The core recommendations can be offered to all patients and a choice can be made
from the other evidence based and cost effective recommendations. The knowledge that
osteoarthritis is a dynamic process which does include the potential for repair if adverse factors are

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Osteoarthritis
minimized, in addition to the many different interventions should allow practitioners to give advice
and support which is positive and constructive. The power of the therapeutic effect of the
practitioner- patient relationship must not be forgotten. Good communication skills imparting
accurate information honestly and sensitively and in a positive way greatly enhance the ability of the
patient to cope. Conversely, negative practitioner attitudes to osteoarthritis can increase the distress
experienced.
Joint protection
These guidelines indirectly address the concept of joint protection by looking specifically at evidence
bases for single interventions. The principles are:
 Resting inflamed joints by reducing loading, time in use and repetitions.
 Using the largest muscles and joints that can do the job. For example, standing up from a chair
using hips and knees rather than pushing up with hands.
 Using proper movement techniques for lifting, sitting, standing, bending and reaching.
 Using appliances, gadgets and modifications for home equipment to minimise stress on joints.
Examples include raising the height of a chair to make standing and sitting easier, using a smaller
kettle with less water, boiling potatoes in a chip sieve to facilitate removal when cooked.
 Planning the week ahead to anticipate difficulties.
 Using biomechanics to best effect. This will include good posture, aligning joints correctly, and
avoiding staying in one position for a long time.
 Balancing activity with rest and organising the day to pace activities.
 Simplifying tasks.
 Recruiting others to help.
 Making exercise a part of every day including exercises which improve joint range of movement,
stamina and strength. Exercise should also be for cardiovascular fitness and to maintain or
improve balance.
Pain
Pain is a complex phenomenon. Effective pain relief may require using a number of analgesics or pain
relieving strategies together. The complexity of multiple pain pathways and processes often mean
that two or more treatments may combine synergistically or in a complementary way to act on the
different components of the pain response. This technique is known as balanced, or multi-modal
analgesia.
By tackling pain early and effectively it is hoped that the development of chronic pain can be stopped
but more work needs to be done in this area. Timing of analgesia is important. Regular analgesia will
be appropriate if the pain is constant. Pain with exertion can be helped by taking the analgesia
before the exercise. Some patients will need multi-disciplinary care for their joint pain. For these
people long term opioids can be of benefit (see section 9).

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Osteoarthritis
Education and self-management
7 Education and self-management

7.1 Patient information
7.1.1 Clinical Introduction
There is limited disease-specific evidence on the benefits of information provision for osteoarthritis.
It is essential that the consultation is one of information sharing and achieving concordance in the
treatment regimes suggested.90,136 The recognition that the patient is being treated as an individual
and not a disease state will be imperative to improved communication and better outcomes.123
People will vary in how they adjust to their condition or instigate changes as a result of the
information and advice provided. This is likely to depend upon a number of factors:
 The disease severity and levels of pain, fatigue, depression, disability or loss of mobility
 Prior knowledge and beliefs about the condition
 The social and psychological context at the time
 Health beliefs and learnt behaviours.

We looked for studies that investigated:
 the effectiveness of patient information provision / education methods compared to each other
or to no information / education;
 the effectiveness of patient self-management programmes compared to each other or no self-
management;
 both with respect to symptoms, function, quality of life.
Due to the large volume of evidence, studies were excluded if they used a mixed arthritis population
of which <75% had osteoarthritis or if population was not relevant to the UK.
Two systematic reviews and meta-analyses (MA),74,435 8 RCTs,54,55,186,235,274,334,340,476 1 implementation

study103 and 1 observational study176 were found on patient education and self-management
methods. Two of these studies235,340 were excluded due to methodological limitations.
The first MA74 included 14 RCTs on osteoarthritis self-management programmes compared to usual
care or control programmes (attending classes which were unrelated to osteoarthritis self–
management). Follow-up was between 4-6 months for all studies. Quality of the included RCTs was
assessed but the results of this are not mentioned. The MA pooled together all data for the
outcomes of pain and function.
The second MA435 included 10 RCTs/CCTs on osteoarthritis patient education (information about
arthritis and symptom management) compared to control (types of controls not mentioned). Quality
of the included RCTs was not assessed. The MA pooled together all data for the outcomes of pain
and functional disability. Studies differed with respect to sample size and duration.
The six RCTs not included in the systematic reviews were all randomised, parallel group studies but
differed with respect to:
 Osteoarthritis site (2 RCTs knee, 2 RCTs Hip and/or knee, 2 RCTs not specified).
 Treatment (5 RCTs group sessions of self-management / education programmes, 1 RCT telephone
intervention – treatment counselling and symptom monitoring).

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Osteoarthritis
 Comparison (2 RCTs usual care, 2 RCTs waiting list, 1 RCT education booklet, 1 RCT education
lecture).
 Trial size, blinding and length
The implementation study103 was methodologically sound and compared the effects of a 6-week
knee osteoarthritis self-management programme (N=204 patients) and a 9-week hip osteoarthritis
self-management programme (N=169 patients) with pre-treatment values in patients from urban and
semi-rural communities.
The observational-correlation study was methodologically sound and consisted of giving

questionnaires to, and interviewing, N=61 osteoarthritis patients in order to assess their use of self-
management methods to deal with the symptoms of osteoarthritis.
Table 22: Pain

Assessment Outcome / Effect
Pain outcome Reference Intervention time size
Knee
Pain severity 1 implementation Knee programme (pre-test 6 weeks, end -5.4, p=0.002
103
(VAS, change study (N=204) vs post-test) of Favours
from baseline) intervention intervention
Pain tolerance 1 implementation Knee programme (pre-test 6 weeks, end -3.9, p=0.034
103
IRGL pain scale 1 implementation Knee programme (pre-test 6 weeks, end -0.4, p=0.015
103
(scale 5-25, study (N=204) vs post-test) of Favours
change from intervention intervention
baseline)
334
WOMAC pain 1 RCT (N=100) Therapeutic education and 9 months, 6 NS
functional readaptation months post-
programme (TEFR) + intervention
conventional
(pharmacologic) treatment
vs control (waiting list) +
pharmacologic treatment
476
WOMAC pain 1 RCT (N=193) Education programme 1 month (end NS
(nurse-led) vs control of
(waiting list) group intervention)
and at 1 year
(11 months
post-
intervention).
Hip
Pain severity 1 implementation Hip programme (pre-test 9 weeks, end -4.7, p=0.007
103
Pain tolerance 1 implementation Hip programme (pre-test 9 weeks, end -4.9, p=0.004
103

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Osteoarthritis

IRGL pain scale 1 implementation Hip programme (pre-test 9 weeks, end -0.4, p=0.032
103
(scale 5-25, study (N=169) vs post-test) of Favours
change from intervention intervention
baseline)
Knee and/or hip
54
WOMAC Pain 1 RCT (N=812) self-management 4 months and NS
programme + education 12 months
booklet vs education post-
booklet alone intervention
Unspecified site
435
Pain (weighted 1 MA (9 RCTs), Patient education vs Study Effect size: 0.16,
average N=9 RCTs control duration 95% CI -0.69 to
standardised gain between 1 to 1.02
difference) 42 months No p-values given
74
Pain (Pooled 1 MA (14 RCTs) Self-management 4 to 6 months Effect size: -0.06,
estimate) programmes vs control follow-up 95% CI -0.10 to -
groups (mostly usual care 0.02, p<0.05.
or programme control) Favours
intervention
Effect size
equivalent to
improvement of
<2mm on VAS pain
scale.
186
Knee pain (VAS) 1 RCT (N=297) Self-management 3 months Mean
programme vs usual care post- improvement 3
intervention months: 0.67 (self-
and 21 management) and
months post- 0.01 (usual care),
intervention p=0.023
21 months: 0.39
(self-management)
and –0.48 (usual
care), p=0.004
186
Hip pain (VAS) 1 RCT (N=297) Self-management 3 months NS
programme vs usual care post-
intervention
and 21
months post-
intervention
Table 23: Stiffness

Assessment Outcome /
Stiffness outcome Reference Intervention time Effect size
Knee
334
WOMAC stiffness 1 RCT (N=100) Therapeutic education 9 months, 6 NS
and functional months post-
readaptation programme intervention
(TEFR) + conventional
(pharmacologic)
treatment vs control

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Osteoarthritis
(waiting list) +
pharmacologic
treatment
476
WOMAC stiffness 1 RCT (N=193) Education programme 1 month (end NS
(nurse-led) vs control of intervention)
(waiting list) group and at 1 year
(11 months
post-
intervention).
Knee and/or hip
54
WOMAC stiffness 1 RCT (N=812) Self-management 4 months and NS
programme + education 12 months
Table 24: Function

Function Assessment Outcome / Effect
outcome Reference Intervention time size
Knee
IRGL mobility 1 implementation Knee programme (pre- 6 weeks, end NS
103
scale (scale 7-28, study (N=204) test vs post-test) of intervention
change from
baseline)
334
WOMAC function 1 RCT (N=100) Therapeutic education 9 months, 6 Mean values: 35.3
and functional months post- (TEFR) and 40.9
readaptation intervention (control), p=0.035
programme (TEFR) + Favours
conventional intervention
(pharmacologic)
(waiting list) +
pharmacologic
treatment
476
WOMAC disability 1 RCT (N=193) Education programme 1 month (end NS
(nurse-led) vs control of
and at 1 year
(11 months
post-
intervention).
Hip
IRGL mobility 1 implementation Hip programme (pre- 9 weeks, end NS
103
scale (scale 7-28, study (N=169) test vs post-test) of intervention
change from
baseline)
Knee and/or hip
54
WOMAC physical 1 RCT (N=812) Self-management 4 months and NS
functioning programme + education 12 months
Unspecified site

84
Osteoarthritis
Function Assessment Outcome / Effect

74
Function (pooled 1 MA (14 RCTs) Self-management 4 to 6 months Effect size: -0.06,
estimate) programmes vs control follow-up 95% CI -0.10 to -
groups (mostly usual 0.02, p<0.05).
care or programme Effect size
control) equivalent to
approximately 2
points on the
WOMAC Index.
186
WOMAC index at 1 RCT (N=297) Self-management 3 months post- 3 months: 2.46
3 months post- programme vs usual intervention (self-management)
intervention care and 21 months and -0.53 (usual
(mean post- care), p=0.030
improvement) intervention 21 months: 2.63
(self-management)
and -0.88 (usual
care), p=0.022
Favours
intervention
186
Patient-specific 1 RCT (N=297) Self-management 21 months 0.49 (self-
functional status, programme vs usual post- management) and -
PSFS care intervention 0.05 (usual care),
p=0.026
Favours
intervention
435
Functional 1 MA (9 RCTs), Patient education vs Study duration NS
disability N=9 RCTs control between 1 to
(weighted 42 months
average
standardised gain
difference)
186
Patient-specific 1 RCT (N=297) Self-management 3 months post- NS
functional status, programme vs usual intervention
PSFS care
Table 25: Quality of life

QoL outcome Reference Intervention time size
Knee
334
SF-36 (dimensions of 1 RCT Therapeutic education and 9 months, 6 NS
physical function, (N=100) functional readaptation months post-
physical role, bodily programme (TEFR) + intervention
pain, general health, conventional
social function, (pharmacologic) treatment
emotional role, vs control (waiting list) +
vitality, mental pharmacologic treatment
health)
476
SF-36 (vitality 1 RCT Education programme 1 year (11 Mean difference: -
dimension) (N=193) (nurse-led) vs control months post- 5.5, 95% CI –10.0
(waiting list) group intervention) to –0.9, p<0.05
Favours
intervention
476
SF-36 (vitality 1 RCT Education programme 1 month (end NS

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Osteoarthritis

dimension) (N=193) (nurse-led) vs control of
476
SF-36 subscales 1 RCT Education programme 1 month (end NS
(physical, role (N=193) (nurse-led) vs control of
physical, emotional, (waiting list) group intervention)
social, pain, mental, and at 1 year
general health); (11 months
Arthritis Helplessness post-
Index (AHI) score intervention)
Knee or hip
274
Total AIMS2 health 1 RCT Treatment counselling vs 9 months (end Effect size* 0.36,
status score (N=405) usual care of treatment) 95% CI 0.06 to
0.66, p<0.05
Favours
intervention
274
AIMS2 pain 1 RCT Treatment counselling vs 9 months (end Effect size* 0.44,
dimension (N=405) usual care of treatment) 95% CI 0.08 to
0.80, p<0.05
Favours
intervention
274
AIMS2 physical 1 RCT Treatment counselling vs 9 months (end NS
dimension (N=405) usual care of treatment)
274
AIMS2 affect 1 RCT Treatment counselling vs 9 months (end NS
dimension (N=405) usual care of treatment)
274
AIMS2 physical 1 RCT Symptom monitoring vs 9 months (end Effect size* 0.29,
dimension (N=405) usual care of treatment) 95% CI 0.01 to
0.76, p<0.05
Favours
intervention
274
Total AIMS2 health 1 RCT Symptom monitoring vs 9 months (end NS
status score;AIMS2 (N=405) usual care of treatment)
pain dimension;
AIMS2 affect
dimension
274
Total AIMS2 health 1 RCT Treatment counselling vs 9 months (end mean score 4.1
status score (N=405) symptom monitoring of treatment) (counselling) and
4.2 (monitoring)
Both groups
similar
Knee and/or hip
54
Hospital anxiety and 1 RCT (N=812) Self-management 4 months and Adjusted mean
depression scale programme + education 12 months difference -0.36,
(depression booklet vs education post- 95% CI -0.76 to
component) booklet alone intervention 0.05, p<0.05
Favours
intervention
54
Hospital anxiety and 1 RCT (N=812) Self-management 4 months and Adjusted mean
depression scale programme + education 12 months difference -0.62,
(anxiety component) booklet vs education post- 95% CI -1.08 to -
booklet alone intervention 0.16, p<0.05

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Osteoarthritis

Favours
intervention
54
SF-36 mental and 1 RCT (N=812) Self-management 4 months and NS
physical health programme + education 12 months
components; hospital booklet vs education post-
anxiety and booklet alone intervention
depression scale
Unspecified site
186
Pain-related fear (TSK 1 RCT Self-management 3 months Mean
– 19 item (N=297) programme vs usual care post- improvement 3
questionnaire) intervention months: 2.05 (self-
and 21 management) and
months post- -1.01 (usual care),
21 months: 2.15
(self-
management) and
–1.68 (usual care),
p=0.000
Favours
intervention
186
SF-36 subscales of 1 RCT Self-management 3 months NS
health change, (N=297) programme vs usual care post-
physical functioning intervention
and general health and 21
perception months post-
intervention
55
Beck Depression RCT (N=40) Cognitive-behavioural 10 weeks (end 10 weeks: 8.1,
Inventory, BDI, 6 modification vs education of p=0.008
months (mean intervention) months: 7.6,
difference) and at 2, 6 p=0.006
and 12 6 months: 7.2,
months post- p=0.017
intervention
12 months: 7.0,
p=0.006
Favours
intervention
55
AIMS physical RCT (N=40) Cognitive-behavioural 2 months and 2 months: 2.59,
functioning score modification vs education 6 months p=0.038
(mean difference) post- 6 months: 2.35,
Favours
intervention
55
AIMS psychological RCT (N=40) Cognitive-behavioural 6 months 2.57, p=0.038
status score (mean modification vs education post- Favours
difference) intervention intervention
55
Quality of well-being RCT (N=40) Cognitive-behavioural 10 weeks (end NS
scale (QWB); AIMS modification vs education of
pain score intervention)
and at 2, 6
and 12
months post-

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intervention
55
AIMS psychological RCT (N=40) Cognitive-behavioural 10 weeks (end NS
status modification vs education of
intervention)
and at 2 and
12 months
post-
intervention
55
AIMS physical RCT (N=40) Cognitive-behavioural 10 weeks (end NS
functioning modification vs education of
intervention)
and at 12
months post-
intervention
Table 26: Self-efficacy

Self-efficacy Assessment Outcome / Effect
Knee
Self-efficacy pain 1 implementation Knee programme (pre- 6 weeks, end +0.2, p=0.006
103
(scale 0-5, change study (N=204) test vs post-test) of intervention Favours
from baseline) intervention
Self-efficacy 1 implementation Knee programme (pre- 6 weeks, end NS
103
functioning (scale study (N=204) test vs post-test) of intervention
0-5, change from
baseline) and Self-
efficacy other
symptoms (scale
0-5, change from
baseline)
Knee and/or hip
54
Arthritis self- 1 RCT (N=812) Self-management 4 months and 4 months: Effect
efficacy scale programme + education 12 months size: 1.63, 95% CI
(pain component) booklet vs education post- 0.83 to 2.43, p<0.05
(adjusted mean booklet alone intervention 12 months: Effect
difference) size 0.98, 95% CI
0.07 to 1.89, p<0.05
Favours
intervention
54
Arthritis self- 1 RCT (N=812) Self-management 4 months and 4 months: effect
efficacy scale programme + education 12 months size 1.83, 95% CI
(‘other’ booklet vs education post- 0.74 to 2.92, p<0.05
component) booklet alone intervention 12 months: 1.58,
95% CI 0.25 to 2.90,
p<0.05
Favours
intervention
Table 27: Health service use

Outcome Reference Intervention time size

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Osteoarthritis

Outcome Reference Intervention time size
Knee
334
Mean number of 1 RCT Therapeutic education and 9 months (6 Intervention
visits to the GP (N=100) functional readaptation months post- better
programme (TEFR) + intervention)
conventional
(pharmacologic) treatment
vs control (waiting list) +
pharmacologic treatment
Knee or hip
274
Number of patient 1 RCT Treatment counselling vs 9 months (end Mean visits: 2.7
visits to physicians (N=405) usual care of treatment) (counselling) and
4.3 (usual care),
p<0.01
Favours
intervention
274
Number of patient 1 RCT Symptom monitoring vs 9 months (end NS
visits to physicians (N=405) usual care of treatment)
274
Number of patient 1 RCT Treatment counselling vs 9 months (end Mean visits: 2.7
visits to physicians (N=405) symptom monitoring of treatment) (counselling) and
3.9 (monitoring)
Counselling better
Table 28: Analgesic use

Analgesic use Assessment Outcome / Effect
Knee
Number of 1 implementation Knee programme (pre- 6 weeks, end 8.7 (pre-test) and
103
analgesics taken study (N=204) test vs post-test) of intervention 4.8 (post-test),
per week p=0.036
Favours
intervention
334
Reduction in the 1 RCT (N=100) Therapeutic education 9 months, 6 NS
number of NSAIDs and functional months post-
taken per week readaptation intervention
programme (TEFR) +
conventional
(pharmacologic)
(waiting list) +
pharmacologic
treatment
334
Mean usage of 1 RCT (N=100) Therapeutic education 9 months, 6 Reduced from
analgesics/week and functional months post- baseline in
readaptation intervention intervention but
programme (TEFR) + not control group.
conventional Favours
(pharmacologic) intervention
(waiting list) +
pharmacologic
treatment

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Table 29: Osteoarthritis knowledge

Osteoarthritis
knowledge Assessment Outcome / Effect
Knee
Osteoarthritis 1 implementation Knee programme (pre- 6 weeks, end +1.3, p=0.000
103
knowledge (scale study (N=204) test vs post-test) of intervention Favours
0-10, change from intervention
baseline)
476
Arthritis 1 RCT (N=193) Education programme 1 month (end Only small
knowledge score (nurse-led) vs control of improvement in
(waiting list) group intervention) intervention group
and at 1 year (1 month: +0.2 and
(11 months 1 year: +0.3)
post-
intervention)
Table 30: Use of self-management methods

Use of self-
management
methods
outcome Reference Intervention Outcome / Effect size
Unspecified site
Self- 1 observational Worse day vs typical Initial: 5.0 (worse day) and 4.4 (typical
176
management use study (N=61) day at Initial day), p<0.01
(mean number of assessment and 8 8 months: 4.5 (worse day) and 4.1 (typical
methods used) months follow-up day), p<0.01
Favours worse day (more used)
Most frequently 1 observational - Gentle (low-impact) activity (92%);
176
used study (N=61) Medication (70%);
management Rest (65%);
methods (used
Range of motion exercises (63%)
by >50% of
patients for each
type)
Less popular self- 1 observational - Relaxation (40%);
176
management study (N=61) Thermotherapy, heat or cold (37%);
methods (used Joint protection (25%);
by <50% of
Massage (25%);
patients)
Splinting (23%);
Other methods (5%)
Use of less 1 observational worse day vs typical Favours worse days (more used)
176
popular methods study (N=61) day
Most common 1 observational - Dietary supplements or modifications
176
‘other’ self- study (N=61) (31%); Physical activity (24%); Various
management forms of protective behaviours (19%);
methods Application of liniments to the joints (14%)
Use of cognitive- 1 observational - N=0 (cognitive)
176
strategies or study (N=61) N=2 (relaxation)
relaxation to
distract from
pain and
discomfort

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Osteoarthritis
Use of self-
management
methods
outcome Reference Intervention Outcome / Effect size
Medication to 1 observational - Taken by participants regardless of
176
control study (N=61) symptom intensity
osteoarthritis
Use of passive 1 observational Use on worse days was correlated with
176
methods study (N=61) reported pain, believing one’s pain to be
serious and the number of joints involved
and was associated with more pain over
the last month and poorer role
functioning.

There is a significant body of evidence in the field of social and psychological research on health
behaviours in the context of information giving and health seeking behaviours and subsequent
attitudes to treatments offered.2,59,124 Evidence has demonstrated that patients fail to retain all the
information provided during a consultation. Lay health beliefs, perceived threat of the condition or
treatments prescribed as well as time taken to adjust to the diagnosis all have an effect on an
individual’s ability to retain information and make changes to their health behaviours of concordance
with treatments.
Although it is clear that many patients want more information than they currently receive, not all
people will wish this. The degree to which people may wish to be involved in decisions about their
treatment is likely to vary. Evidence suggests people may adopt one of three approaches when
asked to make treatment decisions on their own;88 those who wish to:
 select their own treatment,
 choose to collaborate with the healthcare professionals in making a decision,
 delegate this responsibility to others.
Patient education is an information giving process, designed to encourage positive changes in

behaviours and beliefs conducive to health.371 Patient education varies in content, length and type of
programme (planned group sessions or tailored one-to-one sessions).
There are three components to patient education:

 General information giving aspects that provide an overview of the condition to aid
understanding and enable discussions about changes in health status.
 Specific information giving to encourage positive health seeking behaviours that can improve
patient self management and outcomes – e.g. exercise in osteoarthritis
 Information giving about benefits and risks to aid informed consent.
There is a professional responsibility to ensure that patients are provided with sufficient and
appropriate information about their condition. Patient education is an integral part of informed
decision making. In addition within the wider context patient education has been advocated as a
way of limiting the impact of a long term condition.110

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7.1.5 Recommendation
7. Offer accurate verbal and written information to all people with osteoarthritis to enhance
understanding of the condition and its management, and to counter misconceptions, such as
that it inevitably progresses and cannot be treated. Ensure that information sharing is an
ongoing, integral part of the management plan rather than a single event at time of
presentation. [2008]
7.2 Decision aids

7.2.1 Introduction
The International Patient Decision Aids Standards (IPDAS) Collaboration describes patient decision
aids as evidence-based tools designed to prepare patients to participate in making specific and
deliberated choices among healthcare options. Patient decision aids do not replace, but may act as
an adjunct to good clinical practice. Patient decision aids are not necessary to deliver good shared
decision-making, but where well developed patient decision aids exist, they facilitate patient
engagement and can be used before, during or after a consultation to enable patient participation.
They are different from patient information leaflets (PILs) which aim to provide information on how a
medicine should be used to patients or consumers.
Decision aids may be used at a variety of time points throughout the person with osteoarthritis
pathway, and surround decisions on every aspect of care including exercise and diet,
pharmacological management and in the consideration of joint replacement. The GDG wished to
ascertain the clinical and cost-effectiveness of any OA specific decision aids that may be utilised to
enable people to participate in the management of their condition..
Update 2014
7.2.2 What is the clinical and cost-effectiveness of decision aids for the management of OA?

Population Adults with a suspected diagnosis of OA
Intervention/s Decision aid
Comparison/s  Patient information leaflet

 No decision-aid
Outcomes  Attributes of the choice
 Attributes of the decision making process
 Decisional conflict
 Patient-practitioner communication
 Participation in decision making
 Proportion undecided
 Satisfaction
 Choice (actual choice implemented, option preferred as surrogate measure)
 Adherence to chosen option
 Health status and quality of life (generic and condition specific)
 Anxiety, depression, emotional distress, regret, confidence
 Consultation length
Study design
Systematic reviews and meta-analyses

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Osteoarthritis
RCTs

We searched for randomised trials and systematic reviews comparing the effectiveness of decision
aids versus patient information leaflets or no decision aids in the management of OA. One Cochrane
Review on patient decision aids for people facing health treatment or screening decisions was
retrieved429, but only one RCT151 in an OA population was included. Two RCTs were included in this
evidence review102,151. All studies included in the review could not be meta-analysed; as they only
reported mean values, and did not report values for SD, SE or range. Evidence from these are
summarised in the clinical GRADE evidence profile below. See also the study selection flow chart in
Appendix D, forest plots in Appendix I, study evidence tables in Appendix G and exclusion list in
Appendix J.
 One study included a population that were considering undergoing total joint replacement102
 The intervention was slightly different in each study: Deacheval (2012) had two intervention
groups, one group received a videobooklet decision aid and one group received a videobooklet
Update 2014
decision aid and undertook adaptive conjoint analysis (ACA); in Fraenkel (2007) the intervention
group undertook adaptive conjoint analysis (ACA). In both studies the comparison group received
an information or education booklet.
The patient experience of NHS services guideline (CG 138) conducted an evidence review (section
10.4.1.5) of the clinical and cost-effectiveness of decision aids versus no intervention, usual care,
alternative interventions, or a combination. As this was a 2011 review of the literature on this topic,
the GDG accepted it for inclusion in the review and did not update the searches due to time and
resource constraints. See section 10.4.2 of CG 138 for full list of recommendations.
Table 32: Summary of studies included in the review

Study Intervention/comparison Population Outcomes Comments
102
DeAcheval 2012 Educational booklet vs People with Decisional conflict
videobooklet patient knee OA
decision aid vs (n=208)
videobooklet decision aid +
ACA
151
Fraenkel 2007 Information leaflet vs People with Confidence in Only means
decision aid (ACA) knee pain decision making, scores
(n=87) perception of reported,
usefulness, arthritis could not
self- efficacy meta-
analyse data
ACA= adaptive conjoint analysis

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Osteoarthritis
Table 33: Clinical evidence profile: Decision aids versus information leaflet (usual care)
Quality assessment No of patients Effect

No of Design Risk of Inconsistency Indirectness Imprecision Other Decision Aid Usual Relative Absolute
studies bias care (95% CI) Quality Importance
Decisional conflict: De Achaval 2012
a
1 randomised Serious N/A No serious N/A Videobooklet Education Videobooklet - MODERATE IMPORTANT
trials indirectness decision aid: leaflet decision aid vs
-21 control - education
Videobooklet 9.5 leaflet:
decision aid + p=<0.001
ACA: -14 Videobooklet
decision aid +
ACA vs
Update 2014
education
leaflet :
94
p=<0.001
Videobooklet
decision aid vs
videobooklet
decision aid +
ACA: NS
Confidence in decision making: Fraenkel 2007
1 a b IMPORTANT
randomised Serious N/A no serious Serious none mean Decision aid vs -
trials indirectness mean score: score: usual care: LOW
32/44 27/44 p=0.001
(n=47) (n=40)
Perception of usefulness: Fraenkel 2007

1 a b IMPORTANT
randomised Serious N/A no serious Serious none mean score: mean Decision aid vs -
trials indirectness 35/45 score: usual care: LOW
21/45
(n=47) P=0.0001
Osteoarthritis

No of Design Risk of Inconsistency Indirectness Imprecision Other Decision Aid Usual Relative Absolute
studies bias care (95% CI) Quality Importance
(n=40)
Update 2014
Arthritis self-efficacy (Acceptability of Decision aid): Fraenkel 2007
a
1 randomised Serious b IMPORTANT
trials N/A no serious Serious none mean score: mean Decision aid vs -
indirectness 26/40 score: usual care: LOW
22/40
(n=47) P=0.02
(n=40)
(a) Outcomes were downgraded by one increment if the weighted average number of serious methodological limitation s across studies was one, and downgraded by two increments if the
weighted average number of serious methodological limitation across studies were two or more. Methodological limitations comprised one or more of the following: unclear allocation
concealment, the lack of blinding, inadequate allowance for drop-outs in the analysis, selective outcome reporting or unadjusted baseline inequality.
(b) Outcomes were downgraded by one increment if the upper or lower 95% CI crossed the lower MID or the upper or lower 95% CI crossed the upper MID. Outcomes were downgraded by two
increments if the upper CI simultaneously crossed the upper MID and the lower CI crossed the lower MID.
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Osteoarthritis

No relevant economic evaluations comparing decision aids with patient information leaflets or no
decision aids were identified.
Clinical
 One study (n=208) suggested that:
o People who used a decision aid alone may have a greater decrease in decisional conflict than
people who received an educational information leaflet only.
o People who used a decision aid with an Adaptive Conjoint Analysis (ACA) task may have a
greater decrease in decisional conflict than people received an educational information leaflet
alone
o There may be no difference in reduction in decisional conflict between people who used a
decision aid alone compared to people who used a decision aid with an ACA task [Moderate
quality]
 One study (n=87) suggested that there may a greater increase in a patient’s confidence in decision
making for OA treatment options in people who used a decision aid compared to people who
received an information leaflet [Low quality].
Update 2014
 One study (n=87) suggested that people with OA who used decision aids may have an increased
preparation for decision making in determining their treatment options compared to people with
OA who received information leaflets [Low quality].
 One study (n=87) suggested that there may be higher self-efficacy in people with OA who used a
decision aid to assess treatment options compared to people who received an information leaflet
[Low quality].
Economic
8. Agree a plan with the person (and their family members or carers as
appropriate) for managing their osteoarthritis. Apply the principles in
Patient experience in adult NHS services (NICE clinical guidance 138) in
Recommendations relation to shared decision-making. [new 2014]
Relative values of The GDG considered that decisional conflict, confidence in decision-making
different and self-efficacy were important outcomes for decision-making.
outcomes
Trade off between Decision aids aim to reduce decisional conflict and serve as a tool for use by
clinical benefits clinicians and patients to facilitate shared decision making. Whilst there was
and harms moderate quality evidence that decision aids may reduce decisional conflict
more than an education leaflet alone, and low quality evidence that patients

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Osteoarthritis
confidence in decision making, self-efficacy and preparation for decision

making are all increased with decision aids, the GDG did not consider that
the decision aids reviewed would support a recommendation.
The DVD decision aid used in DeAcheval et al 2012101 was unavailable for the
GDG to assess its content. The GDG felt that the decision aid used in Frankel
et al 2007151 contained inaccurate information, particularly on the relative
risks of pharmacological interventions, and did not feel the evidence merited
its use in the OA population.
The GDG considered it important to highlight that decision aids should be

used as support tools as part of a discussion with a clinician and not as stand-
alone tools. The GDG agreed that decision aids are helpful, as any relevant
and supportive information has the potential to reassure the patient.
Owing to a paucity of good quality evidence for any given decision aid, and
allied with the fact that the trials used outcomes which were relatively
unknown to the GDG it was difficult to capture the benefit of such a tool.
Therefore, the GDG agreed to refer to the principles of shared decision
making outlined in the patient experience guideline.
Economic Decision aids will have a cost associated with them in terms of the cost of the
considerations product itself, whether in leaflet or DVD format. The form of delivery and
maintenance of the decision aid will also have implications, as for example
some decision aids are already available but may require a licensing cost to
be paid. NHS direct also provides some freely available decision aids online
but these need to be maintained by the NHS.
Update 2014
Costs are also dependent on whether additional time is needed with a
healthcare professional when decision aids are used. For example, adaptive
conjoint analysis (ACA) is a computer based decision aid; this method may
need more consultation time with a healthcare professional. Additionally,
patients with poor computer skills may need assistance to use a computer
based decision aid. Thus, there may be additional costs associated with
delivering decision aids.
It was also noted by the GDG that other web based decision aids exist e.g.
from the National Prescribing Centre (now the NICE Medicines and
Prescribing Centre)
http://www.npc.nhs.uk/therapeutics/pain/musculoskeletal/resources/pda_
musculo_pain.pdf but these would not be picked up through a systematic
literature search. These types of decision aids may have low cost associated
with the delivery of the tool itself, however time may be involved in terms of
working through the tool with a clinician, or discussing the results based on
the patients choices and the implications of those choices with regards to
treatment.
Quality of Two studies were included in the review. Moderate quality evidence showed
evidence that decision aids may reduce decisional conflict more than an education
leaflet alone, and low quality evidence showed that patients’ confidence in
decision making, self-efficacy and preparation for decision making were
increased with use of a decision aid.
Other The GDG were aware of the Cochrane musculoskeletal group decision aids
considerations http://musculoskeletal.cochrane.org/decision-aids, which were derived from

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Osteoarthritis
Cochrane systematic reviews but did not feel that their content was
appropriate for the UK setting. They felt that the guidance within existing
Update 2014
NICE guidance (CG138) better captured appropriate advice for practitioners
rather than recommendation any one tool. The GDG therefore drafted the
recommendation to incorporate a reference to this guidance to ensure that
the principles contained within this guidance was applied to people with
osteoarthritis
7.3 Patient self-management interventions

Self management can be defined as any activity that people undertake to promote health, prevent
disease and enhance self-efficacy. People who are able to recognise and believe in their ability to
control symptoms (self-efficacy) can become more active participants in managing their condition
and thus potentially improve their perceived control over their symptoms. This may improve
concordance with treatment options offered and reducing reliance upon healthcare
interventions.90,93
Providing a framework for patients that encourages self-management is now considered an integral
aspect of care for all long term conditions. Self management principles empower the patient to use
their own knowledge and skills to access appropriate resources and build on their own experiences
of managing their condition. Not all patient will wish to self manage or be able to achieve effective
strategies and practitioners should be aware of these vulnerable groups who may require additional
support.
7.3.2 Evidence base

The evidence for this self-management section was searched and appraised together with that for
patient information (section 7.1).

Educational initiatives that encourage self management strategies should be encouraged although it
has to be recognised that such support appears to have limited effectiveness from eligible UK studies
to date. This may relate to a number of limitations including the range and diversity of outcomes
measured and disparities in severity and site of osteoarthritis. Studies exploring key concepts such
as self efficacy and wider psychological and social factors were lacking. There are also important
additional factors in the context of osteoarthritis as lay - and to some extent healthcare
professionals' - expectations of good outcomes are somewhat negative and access to readily
accessible support and advice are generally poor. These perspectives are likely to influence
outcomes.
The members of this working group have considered these limitations yet accept that with the
expected changes in the population with a doubling of chronic disease and elderly patients by 2020
the healthcare system has to consider encouraging a greater degree of self management principles in
line with current health policy. If longer term outcomes are to be achieved, such as reduction in the
use of health resources, effective use of therapeutic options and more adequately prepared and
informed patients seeking interventions such as joint replacement surgery, then self management
may be an appropriate and cost effective tool.
There will be a range of providers including voluntary and independent sectors who will be offering
self management programmes. These programmes will require a thorough evaluation of outcomes

98
Osteoarthritis
achieved at a time when primary care will also be enhancing the infrastructures and support for
those with osteoarthritis requiring healthcare support.
9. Agree individualised self-management strategies with the person with osteoarthritis. Ensure
that positive behavioural changes, such as exercise, weight loss, use of suitable footwear and
pacing, are appropriately targeted. [2008]
10.Ensure that self-management programmes for people with osteoarthritis, either individually or
in groups, emphasise the recommended core treatments (see recommendation 6), especially
exercise. [2008]
7.4 Rest, relaxation and pacing

It would seem sensible if something hurts to rest it. This may only be true in acute situations and may
not hold for chronic conditions. It is counterproductive to give rheumatoid arthritis patients bed rest.
Muscle loss is a feature of both rheumatoid and osteoarthritis. Pain does not mean harm in many
musculoskeletal conditions. We have looked at the effect of exercise on osteoarthritis especially of
the knee, but where do rest, relaxation and coping strategies fit?

We looked for studies that investigated the efficacy and safety of rest and relaxation compared to no
treatment or other interventions with respect to symptoms, function and quality of life. Three
RCTs159,160,289 were found on relaxation, yoga and listening to music. One RCT159 was excluded due to
methodological limitations. No relevant cohort or case-control studies were found.
Two RCTs did not document blinding or ITT analysis. One RCT160 compared Erikson hypnosis versus
Jacobson relaxation technique or no treatment in N=41 patients with knee and/or hip osteoarthritis
over 2 months with follow-up at 3-6 months. The second RCT289 compared listening to music versus
sitting quietly in N=66 patients with osteoarthritis. The interventions lasted for 14 days.
Symptoms: pain: knee and/or hip
One RCT160 (N=41) found that Jacobson relaxation was significantly better than control (no
treatment) for pain (VAS) at 8 weeks, end of treatment (p<0.05), but there was NS difference
between the two groups at 4 weeks (mid-treatment) and at 3 months and 6 months post-treatment.
(1+)
Symptoms: pain: Unspecified site
One RCT289 (N=66) found that rest and relaxation (sitting and listening to music) was significantly
better than the control (sitting quietly and/or reading) for pre-post test changes of SF-MPQ pain
(VAS) and SF-MPQ pain rating index at day 1, day 7 and at 2 weeks (end of treatment), all p=0.001.
Mean differences: SF-MPQ Pain 23.4, 18.9 and 17.3 respectively, all p=0.001; SF-MPQ pain rating
index –5.1, +3.8 and +2.2 respectively, all p=0.001. ( 1+)

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Osteoarthritis
Withdrawals: Knee and/or shoulder
One RCT160 (N=41) found that Jacobson relaxation and Control (no treatment) were similar for total
number of study withdrawals (N=3, 21% and N=4, 31% respectively). (1+)

There was little evidence in this area. Many of the studies were about modalities not relevant to the
NHS (for example therapeutic touch, playing music).
The GDG felt that it was important to emphasise the role of self-management strategies. As this is
done in Section 7.3 above, no recommendation is made here.
7.5 Thermotherapy
Thermotherapy has for many years been advocated as a useful adjunct to pharmacological therapies.
Ice is used for acute injuries and warmth is used for sprains and strains. It seems appropriate to use
hot and cold packs in osteoarthritis.

We looked for studies that investigated the efficacy and safety of local thermo-therapy versus no
treatment or other interventions with respect to symptoms, function and quality of life in adults with
osteoarthritis. One systematic review and meta-analysis,49 1 RCT138 and 1 non-comparative study283
were found on thermotherapy. No relevant cohort or case-control studies were found. The RCT138
was excluded due to methodological limitations.
The meta-analysis assessed the RCTs for quality and pooled together all data for the outcomes of
symptoms and function.
The meta-analysis included 3 single blind, parallel group RCTs (with N=179 participants) on
comparisons between (ice massage, cold packs) and placebo, electroacupuncture (EA), short wave
diathermy (SWD) or AL-TENS in patients with knee osteoarthritis. Studies included in the analysis
differed with respect to:
 Types of thermotherapy and comparisons sed (1 RCT Ice application; 1 RCT Ice Massage)
 Type of comparison used (1 RCT SWD or placebo SWD; 1 RCT EA, AL-TENS or placebo AL-TENS)
 Treatment regimen (3 or 5 days/week)
 Trial size and length
The non-comparative study283 looked at pre- and post-treatment effects of liquid nitrogen
cryotherapy (3 weeks of treatment) in N=26 patients with knee osteoarthritis.
Table 34: Pain

Knee osteoarthritis
Ice massage
49
Pain at rest, PPI score 1 MA 1 RCT, Ice massage vs week 2, end of NS
N=50 control treatment

100
Osteoarthritis

49
Pain at rest, PPI score 1 MA 1 RCT, Ice massage vs AL- week 2, end of NS
N=50 TENS treatment
49
Pain at rest, PPI score 1 MA 1 RCT, Ice massage vs week 2, end of NS
N=50 electroacupuncture treatment
Ice packs
49
Pain difference 1 MA 1 RCT, Ice packs vs control 3 weeks (end NS
N=26 of treatment)
and at 3
months post-
treatment
Liquid nitrogen cryotherapy (pre-treatment vs post-treatment)
Pain Rating Index Total 1 non- Liquid nitrogen 3 weeks (end p=0.013
(McGill Pain comparative cryotherapy (pre- of treatment) Favours cryotherapy
283
questionnaire, change study , N=26 treatment vs post-
from baseline) treatment)
Present Pain Intensity 1 non- Liquid nitrogen 3 weeks (end p=0.002
(McGill Pain comparative cryotherapy (pre- of treatment) Favours cryotherapy
283
questionnaire, change study , N=26 treatment vs post-
Table 35: Function

Function outcome Reference Intervention time size
Knee osteoarthritis
Ice massage
49
Increasing quadriceps 1 MA 1 RCT, Ice massage vs week 2, end of WMD 2.30, 95% CI
strength) N=50 control treatment 1.08 to 3.52,
p=0.0002
Favours ice massage
49
Knee flexion, ROM 1 MA 1 RCT, Ice massage vs week 2, end of WMD 8.80, 95% CI
(degrees) N=50 control treatment 4.57 to 13.03,
p=0.00005
Favours ice massage
49
50- foot walk time 1 MA 1 RCT, Ice massage vs week 2, end of WMD –9.70, 95% CI
(mins) N=50 control treatment –12.40 to –7.00,
p<0.00001
Favours ice massage
49
Increasing quadriceps 1 MA 1 RCT, Ice massage vs week 2, end of 29% relative
strength N=50 control treatment difference
Ice massage better
49
ROM, degrees (change 1 MA 1 RCT, Ice massage vs week 2, end of 8% relative
from baseline) N=50 control treatment difference – no
clinical benefit for
ice massage
49
50- foot walk time, 1 MA 1 RCT, Ice massage vs week 2, end of 11% relative
mins (change from N=50 control treatment difference – no
baseline) clinical benefit for
ice massage

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49
Knee flexion, ROM 1 MA 1 RCT, Ice massage vs AL- week 2, end of NS
(degrees) N=50 TENS treatment
49
50- foot walk time 1 MA 1 RCT, Ice massage vs AL- week 2, end of NS
(mins) N=50 TENS treatment
49
Increasing quadriceps 1 MA 1 RCT, Ice massage vs AL- week 2, end of WMD –3.70, 95% CI
strength N=50 TENS treatment -5.70 to –1.70,
p=0.0003
Favours AL-TENS
49
Increasing quadriceps 1 MA 1 RCT, Ice massage vs week 2, end of WMD –2.80, 95% CI
strength N=50 electroacupuncture treatment –4.14 to –1.46,
p=0.00004
Favours EA
49
50- foot walk time 1 MA 1 RCT, Ice massage vs week 2, end of WMD 6.00, 95% CI
(mins) N=50 electroacupuncture treatment 3.19 to 8.81,
p=0.00003
Favours EA
49
Knee flexion, ROM 1 MA 1 RCT, Ice massage vs week 2, end of NS
(degrees) N=50 electroacupuncture treatment
Cold packs
49
Change on knee 1 MA 1 RCT, Cold packs vs control after the first NS
circumference N=23 application
(oedema)
49
Change on knee 1 MA 1 RCT, Cold packs vs control after 10 WMD –1.0, 95% CI -
circumference N=23 applications, 1.98 to –0.02,
(oedema) end of p=0.04
treatment Favours ice packs
Liquid nitrogen cryotherapy (pre-treatment vs post-treatment)

Right and left knee 1 non- Liquid nitrogen 3 weeks (end p=0.04 and p=0.02
extension comparative cryotherapy (pre- of treatment) Favours cryotherapy
283
study , N=26 treatment vs post-
treatment)
Right and left 1 non- Liquid nitrogen 3 weeks (end p=0.01 and 0.006
quadriceps strength comparative cryotherapy (pre- of treatment) Favours cryotherapy
283
(respectively). study , N=26 treatment vs post-
treatment)
Right and left knee 1 non- Liquid nitrogen 3 weeks (end NS
flexion. comparative cryotherapy (pre- of treatment)
283
study , N=26 treatment vs post-
treatment)

The evidence base on thermotherapy is limited to three small RCTs, only one of which assesses pain
relief. All the thermotherapy studies in osteoarthritis are on applying cold rather than heat. The RCT
looking at pain found no significant difference between cold thermotherapy and control. The results

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in the RCTs assessing function are mixed when compared with controls, with electro-acupuncture
and with AL-TENS. There is no economic evidence available on the subject.
Despite the scarcity of evidence, in the GDG's experience, local heat and cold are widely used as part
of self-management. They may not always take the form of packs or massage, with some patients
simply using hot baths to the same effect. As an intervention this has very low cost and is extremely
safe. The GDG therefore felt that a positive recommendation was justified.
11.The use of local heat or cold should be considered as an adjunct to core treatments. [2008]

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Non-pharmacological management of osteoarthritis
8 Non-pharmacological management of
osteoarthritis
8.1 Exercise and manual therapy
Exercise is widely used by health professionals and patients to reduce pain152,313 and improve
function. Exercise and physical activity can be targeted at the affected joint(s) and also at improving
general mobility, function, well-being and self efficacy. More intensive exercise can strengthen
muscles around the affected joint. However people often receive confused messages about when to
exercise if they experience pain on physical activity or find that resting eases the pain. Often people
believe that activity ‘wears out’ joints. Patients who have followed an exercise programme
sometimes report they have experienced an exacerbation of their symptoms and are reluctant to
continue. Whilst some people may experience an exacerbation of symptoms the vast majority of
people, including those severely affected, will not have any adverse reaction to controlled
exercise.208 For example patients with significant osteoarthritis can ride a bicycle, go swimming or
exercise at a gym with often no or minimal discomfort.
The goals of prescribed exercise must be agreed between the patient and the health professional.
Changing health behaviour with education and advice are positive ways of enabling patients to
exercise regularly. Pacing, where patients learn to incorporate specific exercise sessions with periods
of rest interspersed with activities intermittently throughout the day, can be a useful strategy.
Analgesia may be needed so that people can undertake the advised or prescribed exercise.
The majority of the evidence is related to osteoarthritis of the knee, few studies have considered the
hip and even fewer hand osteoarthritis. This section looks at the research evidence for different
types of exercise for the joints usually affected by osteoarthritis.
Manual therapies are passive or active assisted movement techniques that use manual force to
improve the mobility of restricted joints, connective tissue or skeletal muscles. Manual therapies are
directed at influencing joint function and pain. Techniques include mobilisation, manipulation, soft
tissue massage, stretching and passive movements to the joints and soft tissue. Manipulation is
defined as high velocity thrusts, and mobilisation as techniques excluding high velocity thrusts,
graded as appropriate to the patient's signs and symptoms. Manual therapy may work best in
combination with other treatment approaches, such as exercise.
8.1.2 Methodological introduction: exercise

We looked firstly at studies on investigating the effects of exercise therapy in relation to:
 sham exercise or no treatment control groups, and
 other osteoarthritis therapies.
Secondly we searched for studies that compared the risks and benefits of different exercise therapies
with no treatment. Due to the high number of studies in this area only randomised controlled trials
were inclused as evidence. Knee osteoarthritis RCTs with N=30 or fewer study completers were also
excluded due to the high number of studies relevant to the osteoarthritis population.

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Land-based exercise
For the first question, we found one meta-analysis of 13 randomised controlled trials (RCTs) dealing
specifically with aerobic and strengthening land-based exercise therapies in the knee osteoarthritis
population 385, and an additional 25 RCTs 41,62,139,148,196,198,205,235,249,258,304,306,307,335,350-
352,379,437,448,468 182 46,153,208
, , of land-based exercise .
Five of these RCTs 62,139,196,205,249 were excluded due to multiple methodological limitations, while the
remaining 16 were included as evidence.
For the second question, we found 10 RCTs that compared different land-based exercise programs to
a no-exercise control group 140,198,263,277,291,306,307,351,352,464. Nine studies were included as evidence, with
one study 464 excluded due to multiple methodological limitations.
Hydrotherapy and manual therapy
Nine RCTs28,80,116,127,149,153,184,192,193,482 were identified on hydrotherapy versus no treatment control or

other land-based exercise programs. Four of these 171,314,482,503 were excluded due to multiple
methodological limitations. One study 80 did not report between-group outcome comparisons
adjusted for baseline values, but was otherwise well-conducted, and so was included as evidence
along with the remaining two studies 28,149.
A further five RCTs 115,115,116,127,193 on manual therapy compared to land-based exercise or a control
group were found. All studies were methodologically sound.
Study quality
Many of the included RCTs on land-based, hydrotherapy and manual therapy categories had the
following methodological characteristics:
 Single-blinded or un-blinded
 Randomisation and blinding were flawed or inadequately described
 Did not include power calculations, had small sample sizes or had no ITT analysis.details
8.1.3 Methodological introduction: manual therapy

We looked for studies that investigated the efficacy and safety of manual therapies versus no
treatment or other interventions with respect to symptoms, function, quality of life in patients with
osteoarthritis. 5 RCTs29,115,193,353,463, one cohort study79 and one non-analytic study271were found on
manual therapy (joint manipulation, mobilisation, stretching, with or without exercise).
The 5 RCTs were all randomized, parallel group studies (apart from 1 study which was cross-over353)
and were methodologically sound. Studies differed with respect to:
 Osteoarthritis site (4 RCTs knee, 1 RCT hip).
 Blinding, sample size, trial duration and follow up.
The two non-RCTs were methodologically sound. The cohort study79 compared the effects of one
session of manual therapy (oscillatory mobilisations of the hip) on symptoms and function versus
pre-treatment values in N=39 patients with knee osteoarthritis. The case-series’ compared the
effects of 2-5 weeks of manual therapy (mobilisation and manipulation) on symptoms and function
versus pre-treatment values in N=7 patients with hip osteoarthritis.

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8.1.4 Evidence statements: land-based exercise
Table 36: Pain

Assessment
Pain outcome Reference Intervention time Outcome / Effect size
Exercise vs control
385
Pain 1 MA , 4 RCTs Aerobic walking vs no- Trial duration: Effect size 0.52, 95%
(N=449) exercise control mean 7.2 CI 0.34 to 0.70, p<0.05
interventions months, range Favours exercise
8 weeks to 2
years
385
Pain 1 MA , 8 RCTs Home-based Trial duration: Effect size 0.32, 95%
(N=2004) quadriceps mean 7.2 CI 0.23 to 0.42, p<0.05
strengthening exercise months, range Favours exercise
vs no-exercise control 8 weeks to 2
interventions years
198
Pain (VAS score) 1 RCT Isokinetic, isotonic, and one year p<0.05
(N=132) isometric exercise vs no follow-up Favours exercise
exercise
437
Self-reported pain 1 RCR (N=94) Exercise (strength 3 months p=0.019
(VAS score) training and home follow-up Favours exercise
exercises) vs no
treatment
437
Observed pain 1 RCR (N=94) Exercise (strength 3 months p=0.047
(HHS pain scale) training and home follow-up Favours exercise
exercises) vs no
treatment
307
Transfer pain 1 RCT Aerobic training 18 months P<0.001
intensity and (N=103) exercise groups vs follow-up Favours exercise
frequency (getting health education
in and out of bed,
chair, car etc)
307
Transfer pain 1 RCT Weight training 18 months P=0.04
intensity and (N=103) exercise groups vs follow-up Favours exercise
frequency (getting health education
in and out of bed,
chair, car etc)
46
Mean overall knee 1 RCT (N=41) Tai-chi exercise vs 9 weeks (mid- Both: p<0.05
pain (VAS) attention control treatment) and Favours exercise
12 weeks (end
of treatment)
46
Mean maximum 1 RCT (N=41) Tai-chi exercise vs 6 weeks (mid- Both: p<0.05
knee pain (VAS) attention control treatment) and Favours exercise
9 weeks (mid-
treatment)
307
Pain for ambulation 1 RCT Aerobic training 18 months NS
intensity and (N=103) exercise groups vs follow-up
frequency health education
307
Pain for ambulation 1 RCT Weight training 18 months NS
intensity and (N=103) exercise groups vs follow-up
frequency health education

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Assessment
448
Pain (KOOS 1 RCT (N=61) Weight-bearing 6 months NS
subscale) exercise vs no follow-up
treatment
468
Pain scores (VAS) 1 RCT Strengthening exercise 9 months NS
(N=183) vs educational advice follow-up.
41
Pain during walking 1 RCT (N=68) Strengthening exercise Study end- NS
(Borg 11-grade vs no treatment point (3
scale) months)
258
Pain (six-point 1 RCT (N=19) Strength training vs study end- NS
rating scale) usual treatment point (6 weeks)
46
Mean overall knee 1 RCT (N=41) Tai-chi exercise vs 3 and 6 weeks NS
pain (VAS) attention control (mid-
treatment) and
4 weeks and 6
weeks post-
treatment
46
Mean maximum 1 RCT (N=41) Tai-chi exercise vs 3 weeks (mid- NS
knee pain (VAS) attention control treatment), at
12 weeks (end
of treatment)
and at 4 weeks
and 6 weeks
post-treatment
153
WOMAC pain 1 RCT Tai-chi exercise vs 0-12 weeks NS
(N=152) attention control (end of
treatment)
Exercise + other therapy vs control or exercise
304
WOMAC pain 1 RCT Diet + exercise (aerobic 18 months p ≤ 0.05
(N=316) and resistance) vs post- Favours diet +
healthy lifestyle randomisation exercise
335
WOMAC pain; pain 1 RCT (N=80) Exercise (isometric, 16 weeks (end all p<0.05
(VAS); walking pain; insotonic, stepping) + of study) Favours exercise +
pain at rest hotpacks + ultrasound hotpacks + ultrasound
vs exercise only
182
WOMAC pain 1 RCT Community 3 months, (2 Mean difference 1.15,
(change from (N=325) physiotherapy + advice weeks post- 95% CI 0.2 to 2.1,
baseline) leaflet vs control (no treatment) p=0.008
exercise, advice leaflet Favours
+ telephone call) physiotherapy +
leaflet
182
Change in pain 1 RCT Community 3 months (2 Mean difference -
severity (NRS) (N=325) physiotherapy + advice weeks post- 0.84, 95% CI -1.5 to -
leaflet vs control (no treatment); 0.2, p=0.01
exercise, advice leaflet
+ telephone call)
182
Change in severity 1 RCT Community 3 months (2 3 months: mean
of main problem (N=325) physiotherapy + advice weeks post- difference -1.06, 95%
(NRS) leaflet vs control (no treatment) and CI -1.8 to -0.3,
exercise, advice leaflet at 6 months (4 p=0.005
+ telephone call) months post- 6 months: mean

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Osteoarthritis
Assessment
treatment) difference -1.22, 95%
CI -2.0 to -0.4,
p=0.002
208
WOMAC pain 1 RCT Rehabilitation 6 months (4.5 Mean difference -
(change from programme months post- 1.01, 95%CI -1.84 to -
baseline) (progressive exercise + treatment) 0.19, p=0.016
group discussion) + Favours intervention
usual primary care vs
usual primary care
182
WOMAC pain, 1 RCT Community 6 months and NS
(change from physiotherapy + advice 12 months
baseline) leaflet vs control (no (approximately
exercise, advice leaflet 4 months and
+ telephone call) 10 months
post-treatment
182
Change in severity 1 RCT Community 12 months NS
of main problem physiotherapy + advice (approximately
(NRS) leaflet vs control (no 10 months
exercise, advice leaflet post-
+ telephone call) treatment).
Table 37: Stiffness

Assessment
Stiffness outcome Reference Intervention time Outcome / Effect size
335
WOMAC stiffness 1 RCT (N=80) exercise (isometric, study endpoint P<0.05
insotonic, stepping) + (16 weeks) Favours intervention
hotpacks + ultrasound
vs exercise only
Table 38: Patient Function

Exercise vs control
385
Self-reported 1 MA , 2 RCTs Aerobic walking vs Trial duration: Effect size: 0.46,
disability (N=385) no-exercise control mean 7.2 95% CI 0.25 to
interventions months, range 8 0.67, p<0.05
weeks to 2 years Favours exercise
385
Self-reported 1 MA , 8 RCTs Home-based Trial duration: Effect size: 0.32,
disability (N=2004) quadriceps mean 7.2 95% CI 0.23 to
strengthening months, range 8 0.41, p<0.05
exercise vs no- weeks to 2 years Favours exercise
exercise control
interventions
198
Self-reported 1 RCT (N=132) Isokinetic, isotonic, one year follow- P<0.05
disability (LI 17 and isometric up Favours exercise
questionnaire) exercise groups vs
no exercise
437
Self-reported 1 RCT (N=94) Exercise (strength 3 months follow- NS
disability (GARS) training and home up
exercises) vs no

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treatment
437
Hip function (Harris 1 RCT (N=94) Exercise (strength 3 months follow- NS
hip score). training and home up
exercises) vs
control
448
Functional 1 RCT (N=61) Weight-bearing 6 months follow- NS
performance exercise vs control up
(no treatment)
468
Level of physical 1 RCT (N=183) Strengthening after 9 months NS
activity (Zutphen exercise vs of follow-up
Physical Activity educational advice
Questionnaire); control group
observed disability
(video of patient
standard tasks)
351
Risk of activities of 1 RCT (N=250) Aerobic exercise vs 18 months Cox proportional
daily living (ADL) attention control follow-up hazards: RR 0.53,
disability (30-item 95%CI 0.33 to
questionnaire) 0.85, p=0.009
Favours exercise
351
Risk of activities of 1 RCT (N=250) Resistance exercise 18 months Cox proportional
daily living (ADL) vs attention control follow-up hazards: RR 0.60,
Favours exercise
351
Risk of moving from a 1 RCT (N=250) Aerobic exercise vs 18 months RR 0.45, 95%CI
non-ADL disabled to attention control follow-up 0.26 to 0.78,
an ADL-disabled state p=0.004
over this period Favours exercise
351
Risk of moving from a 1 RCT (N=250) Resistance exercise 18 months RR 0.53 95%CI
non-ADL disabled to vs attention control follow-up 0.31 to 0.91,
an ADL-disabled state p=0.02
over this period Favours exercise
153
WOMAC function 1 RCT (N=152) Tai-chi exercise vs 0-12 weeks (end Standardised
attention control of treatment) response mean:
0.63, 95% CI 0.50
to 0.76, p<0.05.
Favours exercise
46
WOMAC overall 1 RCT (N=41) Tai-chi exercise vs 9 weeks (mid- p<0.05
score attention control treatment) Favours exercise
46
WOMAC overall 1 RCT (N=41) Tai-chi exercise vs 3 and 6 weeks NS
score attention control (mid-treatment),
at 12 weeks (end
of treatment)
and at 4 weeks
and 6 weeks
post-treatment
448
Activities of daily 1 RCT (N=61) weight-bearing 6 months follow- NS
living scores (KOOS exercise vs control up
subscale) (no treatment)

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304
WOMAC function 1 RCT (N=316) Exercise vs healthy 18 months post- NS
lifestyle randomisation
304
WOMAC function 1 RCT (N=316) Diet vs healthy 18 months post- NS
lifestyle randomisation
304
WOMAC function 1 RCT (N=316) Diet + exercise 18 months post- p<0.05
(aerobic and randomisation Favours exercise
resistance) vs
healthy lifestyle
335
WOMAC function 1 RCT (N=80) Exercise (isometric, study endpoint p<0.05
insotonic, stepping) (16 weeks) Favours
+ hotpacks + intervention
ultrasound vs
exercise only
182
WOMAC function 1 RCT Community 3 months, (2 Mean difference
physiotherapy + weeks post- 3.99, 95% CI 1.2
advice leaflet vs treatment) to 6.8, p=0.008
control (no Favours
exercise, advice intervention
leaflet + telephone
call)
208
WOMAC function 1 RCT Rehabilitation 6 months (4.5 Mean difference
(change from programme months post- -3.33, 95% CI -
baseline) (progressive treatment) 5.88 to -0.78,
exercise + group p=0.01
discussion) + usual Favours
primary care vs intervention
usual primary care
208
WOMAC total 1 RCT Rehabilitation 6 months (4.5 Mean difference
(change from programme months post- -4.59, 95%CI -
baseline) (progressive treatment) 8.30 to -0.88,
exercise + group p=0.015
primary care vs intervention
usual primary care
182
WOMAC function, 1 RCT Community 6 months and 12 NS
(change from physiotherapy + months
baseline) advice leaflet vs (approximately 4
control (no months and 10
exercise, advice months post-
leaflet + telephone treatment)
call)

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Table 39: Examination findings

Examination findings Assessment Outcome / Effect
Exercise vs control
41
Knee flexion and 1 RCT (N=68) Strengthening 3 months (end of NS
extension (ascending exercise vs control study)
steps) groups
41
Step-down ability 1 RCT (N=68) Strengthening 3 months (end of Improved: 38%
exercise vs control study) (exercise) and
groups 12% (control)
Worse: 3%
(exercise) and
24% (control)
Exercise better
437
Stair-climbing 1 RCT (N=94) Exercise (strength 3 months follow- NS
training and home up
exercises) vs
control
153
Stair climb (secs) 1 RCT (N=152) Tai-chi vs attention 0-12 weeks (end Standardised
control of treatment) response mean:
0.36, 95% CI 0.23
to 0.49, p<0.05
Favours exercise
198
Mean peak torque 1 RCT (N=132) Exercise (isokinetic, One-year follow- p<0.05
values for knee isotonic, and up Favours exercise
extensor and flexor isometric exercise)
muscles at 60 and vs no exercise
180 degrees
235
Improvements in 1 RCT (N=72) Exercise (strength Study endpoint Extension and
muscle strength for plus endurance (12 weeks) flexion:p<0.001
leg extensions; leg training) vs no- Bicep curls
flexions; bicep curls treatment p=0.004
Favours exercise
307
Knee mean angular 1 RCT (N=103) Aerobic exercise vs 18 months p=0.04
velocity health education follow-up Favours exercise
control
307
Knee mean angular 1 RCT (N=103) Weight training 18 months NS
velocity exercise vs health follow-up
education control
350
Improvements in 1 RCT (N=137) Exercise (aerobic 3 months (end of 30°: p=0.008
quadriceps strength plus strengthening treatment) 60°: p=0.007
(isometric strength plus stretching) vs Favours exercise
30°and 60° angle) educational advice
control
350
Hamstring strength 1 RCT (N=137) Exercise (aerobic 3 months (end of 30°: NS
plus strengthening treatment) 60°p= 0.013; 30°
plus stretching) vs velocity p=0.017;
educational advice 90° velocity
control p=0.048
Favours exercise

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41
Mean peak torque 1 RCT (N=68) Strengthening Study endpoint NS
values for knee exercise vs control (3 months)
extensor and flexor
muscles
468
Muscle strength for 1 RCT (N=183) Strengthening 9 months follow- NS
knee or hip exercise vs up
educational advice
258
Grip strength 1 RCT (N=19) Strength training vs Study endpoint NS
(dynamometer), usual treatment (6 weeks)
pinch measures
(pinch gauge), and
finger ROM
148
Improvement in 1 RCT (N=316) Exercise (aerobic 18 months post- P<0.0001
walking distance and resistance) vs randomisation Favours exercise
healthy lifestyle
control
304
6 minute walking 1 RCT (N=316) Exercise vs healthy 18 months post- p≤ 0.05
distance lifestyle control randomisation Favours exercise
198
Improvement in 1 RCT (N=132) Exercise (isokinetic, One year follow- All p<0.05
walking speed isotonic, and up Favours exercise
isometric groups) vs
control
307
Walking velocity; 1 RCT (N=103) Aerobic exercise vs 18 months of Walking: p=0.001
absolute and relative education control follow-up Stride: p≤ 0.03
stride length Favours exercise
307
Walking velocity; 1 RCT (N=103) Weight-training vs 18 months of Walking: p=0.03
absolute and relative education follow-up Stride: NS
stride length Favours exercise
350
Improvements in 5- 1 RCT (N=137) Exercise (aerobic + 3 months (end of p=0.0001
minute walking test strengthening + intervention) Favours exercise
stretching) vs
educational advice
41
Free walking speed, 1 RCT (N=68) Strengthening study endpoint NS
step frequency, exercise vs control (3 months)
stride length/lower
extremity length, gait
cycle, range of stance
knee flexion, and
range of swing knee
flexion
437
Walking 20 meters 1 RCT (N=94) Exercise (strength 3 months follow- NS
training and home up
exercises) vs
control
153
50-foot walk time 1 RCT (N=152) Tai-chi vs attention 0-12 weeks (end NS
control of treatment)
306
Area, root mean 1 RCT (N=103) Weight training 18 months of Area and
square of centre of exercise vs healthy follow-up pressure:
pressure and average lifestyle control p<0.001
velocity in the double

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leg stance with eyes Velocity: p=0.001
closed position Favours exercise
306
Area, root mean 1 RCT (N=103) Aerobic exercise vs 18 months of Area and
square of centre of healthy lifestyle follow-up pressure: p=0.02
pressure and average control Velocity: NS
velocity in the double Favours exercise
leg stance with eyes
closed position
306
Measures taken in 1 RCT (N=103) Weight training 18 months of NS
the double-leg stance exercise vs healthy follow-up
with eyes open lifestyle control
position
306
Measures taken in 1 RCT (N=103) Aerobic exercise vs 18 months of NS
the double-leg stance healthy lifestyle follow-up
with eyes open control
position
350
Hamstring and lower 1 RCT (N=137) Exercise (aerobic 3 months (end of p=0.003
back flexibility (sit- plus strengthening treatment) Favours exercise
and-reach test) plus stretching) vs
educational advice
control
437
Timed up and go 1 RCT (N=94) Exercise (strength 3 months follow- p=0.043
performance training and home up Favours exercise
exercises) vs no
intervention control
153
Up and Go time 1 RCT (N=152) Tai-chi vs attention 0-12 weeks (end Standardised
(secs) control of treatment) response mean:
0.32, 95% CI 0.19
to 0.45, p<0.05
Favours exercise
148
Stair-climb time 1 RCT (N=316) Diet plus exercise 18 months p=0.0249
(aerobic plus Favours
resistance vs intervention
healthy lifestyle
control
148
Improvement in 1 RCT (N=316) Diet plus exercise 18 months post- P<0.0001
walking distance (aerobic and randomisation Favours exercise
resistance) vs
healthy lifestyle
control
304
6 minute walking 1 RCT (N=316) Diet + exercise vs 18 months post- p≤ 0.05
distance healthy lifestyle randomisation Favours exercise
control

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Table 40: Quality of Life

Exercise vs control
350
Improvements in 1 RCT (N=137) Exercise (aerobic plus at 3 months Walking/bending:
health status (AIMS2 strengthening plus (end of p=0.03
scale) subsets of stretching) vs treatment) pain: p=0.02
walking and bending educational advice Favours exercise
and arthritis pain control
448
SF-36 physical health 1 RCT (N=61) Weight-bearing exercise follow-up (6 NS
status; SF-36 mental vs no treatment months)
health status
448
improvement in 1 RCT (N=61) Weight-bearing exercise follow-up (6 p=0.02
quality of life scores vs no treatment months) Favours exercise
(KOOS subscale)
148
6-minute walk time 1 RCT (N=316) Exercise (aerobic and 18 months P<0.05
resistance) vs healthy post- Favours exercise
lifestyle control randomisatio
n
352
Lower depression 1 RCT (N=439) Aerobic exercise vs 18 months p<0.001
scores (CES-D scale) education follow-up Favours exercise
over time
352
Lower depression 1 RCT (N=439) Resistance exercise vs 18 months NS
scores (CES-D scale) education follow-up
over time
379
SF-36 composite 1 RCT (N=316) Exercise only vs diet 18 months NS
mental health score only or vs healthy post-
and subsets of vitality lifestyle control randomisatio
and emotional role n.
437
Improvement in 1 RCT (N=94) Exercise (strength 3 months P=0.041
health status (Sickness training and home follow-up
Impact Profile) exercises) vs control
437
Quality of life scores 1 RCT (N=94) Exercise (strength 3 months NS
(VAS and Health- training and home follow-up
related QOL scores) exercises) vs no
intervention control
153
SF-12 version 2, 1 RCT (N=152) Tai-chi vs attention 0-12 weeks Standardised
physical component control (end of response mean:
treatment) 0.25, 95% CI 0.12
to 0.38, p≤0.05
Favours exercise
153
SF-12 version 2, 1 RCT (N=152) Tai-chi vs attention 0-12 weeks NS
mental component; control (end of
Depression, Anxiety treatment)
and Stress scale
(DASS21) components
of anxiety, stress and

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depression

148
Improvement in 1 RCT (N=316) Diet + exercise (aerobic 18 months Self-efficacy:
mobility-related self- and resistance) vs post- p=0.0035
efficacy; stair-climb; 6- healthy lifestyle control randomisatio Stair: p=0.005
minute walk time n Walk: p=0.0006
favours
intervention
379
SF-36 composite 1 RCT (N=316) Diet plus exercise 18 months all p<0.01
physical health score (aerobic and resistance) post- Favours
and subscales of vs healthy lifestyle randomisatio intervention
physical role, general control n
health and social
functioning
379
SF-36 subscale body 1 RCT Diet + exercise (aerobic 18 months Both: p<0.04
pain and resistance) vs post- Favours diet +
exercise vs control randomisatio exercise
n
379
SF-36 composite 1 RCT (N=316) Exercise (aerobic and 18 months NS
physical health score resistance) vs healthy post-
and subscales of lifestyle control randomisatio
physical role, general n
health and social
functioning
379
Patient satisfaction 1 RCT (N=316) Diet + exercise (aerobic 18 months P<0.01
with physical function and resistance) vs post- Favours
(SF-36) healthy lifestyle control randomisatio intervention
n
379
Patient satisfaction 1 RCT (N=316) Diet + exercise (aerobic 18 months P<0.01
with physical function and resistance) vs diet post- Favours
(SF-36) randomisatio intervention
n
379
Patient satisfaction 1 RCT (N=316) Exercise (aerobic and 18 months P<0.01
with physical function resistance) vs healthy post- Favours
(SF-36) lifestyle control randomisatio intervention
n
379
SF-36 composite 1 RCT (N=316) Diet + exercise (aerobic 18 months NS
mental health score and resistance) vs diet post-
and subsets of vitality only or vs exercise only randomisatio
and emotional role or vs healthy lifestyle n.
control
208
HAD anxiety (change 1 RCT Rehabilitation 6 months (4.5 Mean difference
from baseline) programme (progressive months post- -0.65, 95%CI -
exercise + group treatment) 1.28 to -0.02,
discussion) + usual p=0.043
primary care vs usual Favours
primary care intervention
208
HAD depression 1 RCT Rehabilitation 6 months (4.5 NS
(change from programme (progressive months post-
baseline) exercise + group treatment)

115
Osteoarthritis

discussion) + usual
primary care vs usual
primary care
208
MACTAR score – QoL 1 RCT Rehabilitation 6 months (4.5 Mean difference
(change from programme (progressive months post- 2.20, 95%CI 0.36
baseline) exercise + group treatment) to 4.04, p=0.019
primary care vs usual intervention
primary care
Table 41: Use of concomitant medication

Use of concomitant Assessment Outcome / Effect
medication outcome Reference Intervention time size
Exercise vs control
468
Use of paracetamol 1 RCT (N=183) Strengthening exercise 9 months 0.32, mean
vs educational advice follow-up difference –17%;
95%CI –30% to –
3%, p<0.05
Favours Exercise
468
Use of NSAIDs. 1 RCT (N=183) strengthening exercise 9 months NS
vs educational advice follow-up
182
Self-reported use of 1 RCT Community over 6 Mean difference
NSAIDs physiotherapy + advice months (up 15%, 95% CI 2 to
leaflet vs control (no to 4-months 28, p=0.02
exercise, advice leaflet + post- Favours
telephone call) treatment) Intervention
182
Self-reported use of 1 RCT Community over 6 Mean difference
analgesia physiotherapy + advice months (up 16%, 95% CI 3 to
leaflet vs control (no to 4-months 29, p=0.02
exercise, advice leaflet + post- Favours
telephone call) treatment) intervention

116
Osteoarthritis
8.1.5 Evidence statements: comparing different land-based exercise regimens
Table 42:Pain
Exercise vs control / other exercise
291
Reductions in pain 1 RCT (N=214) Home + class-based One year of VAS: p<0.001
scores (VAS and exercise vs home-based follow-up WOMAC:
WOMAC) exercise p=0.036
Favours Home +
class exercise
140
Reductions in pain 1 RCT (N=44) Progressive resistance Study p<0.05
(AIMS2) exercise vs isokinetic endpoint (6 Favours
exercise weeks) resistance
exercise
140
Pain severity (VAS, 1 RCT (N=44) Progressive resistance Study NS
WOMAC); night pain exercise vs isokinetic endpoint (6
and pain on standing exercise weeks)
(Lequesne Index)
198
Reduction in pain (VAS 1 RCT (N=132) Isotonic exercise vs One-year p<0.05
score) isokinetic and isometric follow-up Favours isotonic
exercise exercise
307
Reductions in intensity 1 RCT (N=103) Aerobic exercise vs 18 months Both: p<0.001
and frequency of health education control follow-up Favours exercise
transfer pain (getting
in and out of bed,
chair, car etc)
307
Reductions in intensity 1 RCT (N=103) Weight training exercise 18 months Both: p=0.04
and frequency of vs health education follow-up Favours exercise
transfer pain (getting control
in and out of bed,
chair, car etc)
307
Intensity and 1 RCT (N=103) aerobic exercise vs 18 months NS
frequency of health education control follow-up
ambulation pain
307
Intensity and 1 RCT (N=103) Weight training exercise 18 months NS
frequency of vs health education follow-up
ambulation pain control
307
Intensity and 1 RCT (N=103) Weight training exercise 18 months NS
frequency of vs aerobic exercise follow-up
ambulation pain
263
WOMAC pain 1 RCT (N=32) Open kinetic chain study NS
exercise vs closed endpoint (6
kinetic chain exercise weeks)
277
Pain scores (AIMS2, 1 RCT (N=39) High intensity vs low study NS
VAS, WOMAC) intensity aerobic endpoint (10
exercise weeks)

117
Osteoarthritis
Table 43: Stiffness

Stiffness outcome Reference Intervention time size
291
WOMAC stiffness 1 RCT (N=214) Home + class-based One year of NS
exercise vs home-based follow-up
exercise
140
WOMAC stiffness; 1 RCT (N=44) Progressive resistance Study NS
Joint stiffness exercise vs isokinetic endpoint (6
(Lequesne’s scale) exercise weeks)
263
WOMAC stiffness 1 RCT (N=32) Open kinetic chain Study NS
exercise vs closed endpoint (6
Table 44: Patient function

Patient function Assessment Outcome / Effect
291
Aggregate locomotor 1 RCT (N=214) home + class-based one year of function: p<0.001
function score; exercise vs home-based follow-up WOMAC:
WOMAC function exercise p=0.014
Favours Home +
class exercise
140
functionality 1 RCT (N=44) progressive resistance study NS
(Lequesne Index); exercise vs isokinetic endpoint (6
physical function exercise weeks)
140
social activity (AIMS2) 1 RCT (N=44) progressive resistance study p<0.05
exercise vs isokinetic endpoint (6 Favours
exercise weeks) resistance
exercise
140
AIMS2 items (self- 1 RCT (N=44) progressive resistance study NS
care, mobility, exercise vs isokinetic endpoint (6
walking, family exercise weeks)
support, level of
tension, mood and
household tasks)
items; daily activities
scores (Lequesne
Index)
263
WOMAC physical 1 RCT (N=32) open kinetic chain study NS
function exercise vs closed endpoint (6
351
risk of activities of 1 RCT (N=250) aerobic exercise vs 18 months Cox proportional
Favours exercise
351
risk of activities of 1 RCT (N=250) resistance exercise vs 18 months Cox proportional
Favours exercise

118
Osteoarthritis
Patient function Assessment Outcome / Effect

351
Cumulative incidence 1 RCT (N=250) aerobic exercise vs 18 months Aerobic: 36.4%
of ADL disability resistance exercise follow-up Resistance:
37.8%
Both groups
similar

Examination findings Assessment Outcome /
outcome Reference Intervention time Effect size
291
strength and range of 1 RCT (N=214) home + class-based one year of NS
knee flexion measures exercise vs home- follow-up
based exercise
291
balance scores 1 RCT (N=214) home + class-based one year of NS
exercise vs home- follow-up
based exercise
140
gains in 90° peak torque 1 RCT (N=44) progressive resistance study both p<0.05
and 90° torque body exercise vs isokinetic endpoint (6 Favours
weight exercise weeks) isokinetic
exercise
140
all other flexor/extensor 1 RCT (N=44) progressive resistance study NS
muscle strength ratios exercise vs isokinetic endpoint (6
(60-180° peak torque, 60- exercise weeks)
180° peak torque body
weight, 60-180° total
work, and 60-180° total
work body weight)
140
walking time 1 RCT (N=44) progressive resistance study NS
(chronometer), walking exercise vs isokinetic endpoint (6
distance and transfer exercise weeks)
(both Lequesne scale)
198
mean peak torque for 1 RCT (N=132) Isometric exercise vs one-year all p<0.05
knee extensor muscles in isotonic and isokinetic follow-up Favours
concentric and eccentric exercise isometric
contraction at 60° and exercise
flexor muscles in
eccentric contraction at
60°
198
All other mean peak 1 RCT (N=132) isokinetic exercise vs one-year p<0.05
torque values (knee isotonic and isometric follow-up Favours
flexors in concentric exercise isokinetic
contraction at 60°, knee exercise
flexor and extensor
muscles in concentric
and eccentric contraction
at 180°)
198
walking speed 1 RCT (N=132) isokinetic exercise vs one-year P<0.05
isotonic and isometric follow-up Favours
exercise isokinetic
307
knee mean angular 1 RCT (N=103) aerobic exercise vs 18 months P=0.04

119
Osteoarthritis

velocity health education follow-up Favours exercise
control
307
knee mean angular 1 RCT (N=103) weight training 18 months NS
velocity exercise vs health follow-up
education control
307
walking velocity; 1 RCT (N=103) aerobic exercise vs 18 months Velocity:
absolute and relative health education follow-up p=0.001
stride control Stride: p≤ 0.03
Favours exercise
307
walking velocity 1 RCT (N=103) weight training 18 months p=0.03
exercise vs health follow-up Favours exercise
education control
307
absolute and relative 1 RCT (N=103) weight training 18 months NS
stride exercise vs aerobic follow-up
exercise
307
area, root mean square 1 RCT (N=103) weight training 18 months Area and
of centre of pressure and exercise vs aerobic follow-up pressure: both
average velocity in the exercise p<0.001
double leg stance with Velocity:
eyes closed position p=0.001
Favours exercise
307
area, root mean square 1 RCT (N=103) aerobic exercise vs 18 months Area and
of centre of pressure in health education follow-up pressure: both
the double leg stance control p=0.02
with eyes closed position Favours exercise
307
average velocity in the 1 RCT (N=103) aerobic exercise vs 18 months NS
double leg stance with health education follow-up
eyes closed position control
307
area, root mean square 1 RCT (N=103) weight training 18 months NS
of centre of pressure exercise vs aerobic follow-up
measures taken in the exercise
double-leg stance with
eyes open position.
307
area, root mean square 1 RCT (N=103) aerobic exercise vs 18 months NS
of centre of pressure health education follow-up
measures taken in the control
eyes open position.
307
more balance time spent 1 RCT (N=103) aerobic exercise vs 18 months p=0.016
in single-leg stance with health education follow-up Favours exercise
eyes open position control
307
more balance time spent 1 RCT (N=103) weight training 18 months NS
in single-leg stance with exercise vs aerobic follow-up
eyes open position exercise
307
All other measures taken 1 RCT (N=103) aerobic exercise vs 18 months NS
in single-leg stance eyes health education follow-up
open and shut positions control
307
All other measures taken 1 RCT (N=103) weight training 18 months NS
in single-leg stance eyes exercise vs aerobic follow-up

120
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open and shut positions exercise
307
area, root mean square 1 RCT (N=103) weight training 18 months NS
of centre of pressure exercise vs aerobic follow-up
measures taken in the exercise
eyes open position.
307
All other measures taken 1 RCT (N=103) weight training 18 months NS
in single-leg stance eyes exercise vs aerobic follow-up
open and shut positions exercise
263
mean peak torque and 1 RCT (N=32) open kinetic chain study NS
mean torque exercise vs closed endpoint (6
277
timed chair rise, 6-metre 1 RCT (N=39) high intensity vs low study NS
walking distance, and intensity aerobic endpoint (10
gait performance exercise weeks)
(AIMS2)
277
aerobic capacity 1 RCT (N=39) high intensity vs low study NS
intensity aerobic endpoint (10
exercise weeks)

QoL outcome Reference Intervention time Effect size
291
SF-36 physical health 1 RCT (N=214) home + class-based one year of NS
status, emotional and exercise vs home- follow-up
mental health status and based exercise
physical function scales
291
SF-36 pain 1 RCT (N=214) home + class-based one year of p=0.003
exercise vs home- follow-up Favours home +
based exercise class exercise
140
improvement in SF-36 1 RCT (N=44) progressive resistance study p<0.05
post treatment pain exercise vs isokinetic endpoint (6 Favours
scores and SF-36 pain exercise weeks) resistance
score exercise
140
All other physical health 1 RCT (N=44) progressive resistance study NS
quality of life outcomes exercise vs isokinetic endpoint (6
(SF-36: physical function, exercise weeks)
physical role, health, and
vitality scales); SF-36
mental health status
(social, emotional, role
physical and mental
scales)
352
lower depression scores 1 RCT (N=439) aerobic exercise vs 18 months of p<0.001
(CES-D scale) education control follow-up favours exercise
352
lower depression scores 1 RCT (N=439) Resistance exercise vs 18 months of NS
(CES-D scale) education control follow-up

121
Osteoarthritis
8.1.6 Evidence statements: hydrotherapy
Table 47: Pain

Pain outcome Reference Intervention time Effect size
192
Pain on movement (VAS) 1 RCT ) (N=71) Aquatic exercise vs no 6 weeks (end effect size 0.28,
exercise (usual care) of p<0.001
treatment) Favours exercise
192
WOMAC Pain 1 RCT ) (N=71) Aquatic exercise vs no 6 weeks (end effect size 0.24,
exercise (usual care) of p=0.003
153
WOMAC Pain 1 RCT (N=152) Tai-chi vs attention 0-12 weeks Standardised
control (end of response mean:
treatment) 0.43, 95% CI
0.30 to 0.56,
p<0.05
Favours exercise
80
WOMAC pain 1 RCT (N=312) Hydrotherapy vs usual 1 year p<0.05
care Favours exercise
80
WOMAC pain 1 RCT (N=312) Hydrotherapy vs usual 18 months NS
care
149
WOMAC pain 1 RCT (N=105) Hydrotherapy vs land- study NS
based gym exercises or endpoint (6
attention control weeks)
Table 48: stiffness

192
WOMAC stiffness 1 RCT ) (N=71) Aquatic exercise vs no 6 weeks (end effect size 0.24,
80
WOMAC stiffness 1 RCT (N=312) Hydrotherapy vs usual 1 year (end NS
care of
treatment)
and 18
months (6
months post-
treatment)
149
WOMAC stiffness 1 RCT (N=105) Hydrotherapy vs land- study NS

122
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Function outcome Reference Intervention time Effect size
28
function, disability and 1 RCT (N=249) aquatic exercise vs 20 weeks of p=0.02
pain scores (HAQ) usual care no-exercise treatment Favours exercise
control
192
WOMAC function 1 RCT ) (N=71) Aquatic exercise vs no 6 weeks (end effect size 0.08,
exercise (usual care) of p<0.001
192
Six minute walk test 1 RCT ) (N=71) Aquatic exercise vs no 6 weeks (end effect size 0.01,
153
WOMAC Function 1 RCT (N=152) Tai-chi vs attention 0-12 weeks Standardised
0.49 to 0.75,
p<0.05.
Favours exercise
192
Physical Activity Scale for 1 RCT ) (N=71) Aquatic exercise vs no 6 weeks (end NS
the Elderly (PASE); Timed exercise (usual care) of
up and go test; Step test. treatment)
80
WOMAC physical 1 RCT (N=312) Hydrotherapy vs usual 1 year (end p<0.05
function care of Favours exercise
treatment)
80
WOMAC physical 1 RCT (N=312) Hydrotherapy vs usual 18 months(6 NS
function care months post-
treatment)
149
WOMAC function 1 RCT (N=105) Hydrotherapy vs land- study NS

192
Hip abductor strength 1 RCT ) (N=71) Aquatic exercise vs no 6 weeks (end Left: effect size
exercise (usual care) of 0.07, p=0.011;
treatment) Right: effect size
0.16, p=0.012
Favours exercise
192
Quadriceps muscle 1 RCT ) (N=71) Aquatic exercise vs no 6 weeks (end NS
strength exercise (usual care) of
treatment)
80
improvement in stair 1 RCT (N=312) Hydrotherapy vs usual 1 year (end p<0.05
ascent and stair descent care of Favours exercise
treatment)
153
Stair climb (secs) 1 RCT (N=152) Tai-chi vs attention 0-12 weeks Standardised
0.42 to 0.68,

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p<0.05.
Favours exercise
80
improvement in stair 1 RCT (N=312) Hydrotherapy vs usual 18 months (6 NS
ascent and stair descent care months post-
treatment)
80
hamstring and 1 RCT (N=312) Hydrotherapy vs usual 1 year (end NS
quadriceps muscle care of
strength treatment)
and 18
months (6
months post-
treatment)
80
8-foot walk 1 RCT (N=312) Hydrotherapy vs usual 1 year (end NS
care of
treatment)
80
8-foot walk 1 RCT (N=312) Hydrotherapy vs usual 18 months (6 ES 0.23, 95%CI
care months post- 0.00 to 0.45
treatment) Favours exercse
153
50-foot walk time 1 RCT (N=152) Tai-chi vs attention 0-12 weeks Standardised
0.36 to 0.62,
p<0.05
Favours exercise
149
improvements in right 1 RCT (N=105) gym exercises vs study p=0.030
quadriceps muscle hydrotherapy endpoint (6
strength weeks)
149
improvements in right 1 RCT (N=105) gym exercises vs study p<0.001
quadriceps muscle attention control endpoint (6
strength weeks)
149
improvements in left 1 RCT (N=105) gym exercises or vs study p=0.018
strength weeks)
149
improvements in left 1 RCT (N=105) Hydrotherapy vs study p<0.001
strength weeks)
149
Improvements in walking 1 RCT (N=105) Hydrotherapy vs study P=0.048
distance attention control endpoint (6 Favours
weeks) hydrotherapy
149
Improvements in walking 1 RCT (N=105) Gym exercise vs study NS
distance attention control endpoint (6
weeks)
149
walking speed 1 RCT (N=105) Gym exercise vs study p=0.009
attention control endpoint (6 Favours exercise
weeks)
149
walking speed 1 RCT (N=105) Hydrotherapy vs study NS
attention control endpoint (6
weeks)
153
Up and Go time (secs) at 1 RCT (N=152) Tai-chi vs attention 0-12 weeks Standardised

124
Osteoarthritis

0-12 weeks, end of control (end of response mean:
treatment treatment) 0.76, 95% CI
0.63 to 0.89,
p<0.05.
Favours exercise

149
Self-efficacy pain and 1 RCT (N=105) hydrotherapy, land- study NS
self-efficacy function based gym exercises vs endpoint (6
scores (Arthritis Self- attention control weeks)
Efficacy Scale), SF-12
mental component
scores
149
Improvement in self- 1 RCT (N=105) hydrotherapy vs study p=0.006
efficacy satisfaction score control endpoint (6 Favours exercise
(Arthritis Self-Efficacy weeks)
Scale)
149
Arthritis Self-Efficacy 1 RCT (N=105) hydrotherapy vs study NS
Scale dimensions of: Self- control endpoint (6
efficacy pain; self-efficacy weeks)
function; Improvement in
self-efficacy satisfaction
score
149
SF-12 physical 1 RCT (N=105) hydrotherapy vs study Exrecise
component score control endpoint (6 significantly
weeks), better (p value
not given)
149
SF-12 physical and 1 RCT (N=105) hydrotherapy vs study NS
mental component control endpoint (6
scores weeks)
28
improved health status 1 RCT (N=249) aquatic exercise vs 20 weeks p=0.02
(Quality of Well-Being usual care (no-exercise) (end of Favours exercise
scale treatment)
28
improved quality of life 1 RCT (N=249) aquatic exercise vs 20 weeks p=0.01
scores (Arthritis QOL,) usual care (no-exercise) (end of Favours exercise
treatment)
192
AQoL 1 RCT ) (N=71) Aquatic exercise vs no 6 weeks (end effect size 0.17,
treatment) Favours exercsie
80
SF-36 dimensions of: 1 RCT (N=312) Hydrotherapy vs usual 1 year (end NS
vitality, general health, care of
physical function and treatment)
physical role and at 18
months (6
months post-
treatment)
153
SF-12 version 2, physical 1 RCT (N=152) Tai-chi vs attention 0-12 weeks Standardised
component control (end of response mean:

125
Osteoarthritis
0.21 to 0.47,
p<0.05.
Favours exercise
80
SF-36 pain 1 RCT (N=312) Hydrotherapy vs usual 1 year (end p<0.05
care of Favours exercise
treatment)
80
SF-36 pain 1 RCT (N=312) Hydrotherapy vs usual 18 months (6 NS
care months post-
treatment)
153
SF-12 version 2, mental 1 RCT (N=152) Tai-chi vs attention 0-12 weeks NS
component summary and control (end of
Depression, Anxiety and treatment)
Stress scale (DASS21)
components of anxiety,
stress and depression
8.1.7 Evidence statements: exercise vs manual therapy
Table 52: Pain

Symptoms outcome Reference Intervention time Effect size
Manual therapy vs other exercise
193
Improvement in 1 RCT (N=109) manual therapy vs study OR 1.92, 95%CI
participants’ main strengthening exercise endpoint (5 1.30 to 2.60
symptoms (either pain, weeks)
stiffness, walking
disability measured by
VAS)
193
pain at rest (VAS) 1 RCT (N=109) manual therapy vs study 5 weeks: p<0.05
strengthening exercise endpoint (5 6 months: NS
weeks) and
6 months
follow-up
193
walking pain (VAS) 1 RCT (N=109) manual therapy vs study Both: p<0.05
strengthening exercise endpoint (5
weeks) and
6 months
follow-up
193
starting stiffness (VAS) 1 RCT (N=109) manual therapy vs study p<0.05
strengthening exercise endpoint (5
weeks)
193
starting stiffness (VAS) 1 RCT (N=109) manual therapy vs 6 months NS
strengthening exercise follow-up

126
Osteoarthritis

Function outcome Reference Intervention time Effect size
193
Harris Hip scores 1 RCT (N=109) manual therapy vs study Both: p<0.05
strengthening exercise endpoint (5 Favours manual
weeks) and
6 months
follow-up
127
improvements in 1 RCT (N=66) kinaesthesia + study p=0.042
WOMAC physical balancing + endpoint (8 Favours manual
function scores strengthening exercises weeks)
vs strengthening
exercises
115
improvement in mean 1 RCT (N=83) manual therapy + study mean
total WOMAC scores strengthening exercise endpoint (8 improvement
vs control group (sub- weeks) 599mm, 95%CI
therapeutic US) 197 to 1002mm
116
improvement in total 1 RCT (N=134) clinic-based manual 1 year 32% (manual) vs
WOMAC scores (change therapy + follow-up 28% (home)
from baseline) strengthening exercises
vs home-based

193
walking speed 1 RCT (N=109) manual therapy vs study p<0.05
strengthening exercise endpoint (5 Favours manual
weeks)
193
walking speed 1 RCT (N=109) manual therapy vs 6 months NS
127
10 stairs climbing time 1 RCT (N=66) kinaesthesia + study p<0.05
balancing + endpoint (8 Favours manual
strengthening exercises weeks)
vs strengthening
exercises
127
Improvement in 10 1 RCT (N=66) kinaesthesia + study p=0.039
metre walking time balancing + endpoint (8 Favours manual
vs strengthening
exercises
115
Improvement in mean 6- 1 RCT (N=83) manual therapy + study mean
minute walk distance strengthening exercise endpoint (8 improvement
vs control group (sub- weeks) 170 metres,
therapeutic US) 95%CI 71 to
270m
116
Improvement in mean 6- 1 RCT (N=134) clinic-based manual study Both groups the
minute walking test therapy + endpoint (4 same (9%
distance strengthening exercises weeks) improvement)
vs home-based

127
Osteoarthritis

193
SF-36 role physical 1 RCT (N=109) manual therapy vs study P<0.05
strengthening exercise endpoint (5 Favours Manual
weeks)
193
SF-36 role physical 1 RCT (N=109) manual therapy vs 6 months NS
193
SF-36 bodily pain and 1 RCT (N=109) manual therapy vs study NS
physical function strengthening exercise endpoint (5
weeks) and 6
months
follow-up
127
SF-36 vitality and 1 RCT (N=66) kinaesthesia + study P=0.046
energy/fatigue scores balancing + endpoint (8 Favours manual
vs strengthening
exercises
127
SF-36 physical function 1 RCT (N=66) kinaesthesia + study p=0.006
balancing + endpoint (8 Favours manual
vs strengthening
exercises
127
SF-36 physical role 1 RCT (N=66) kinaesthesia + study p=0.048
limitations balancing + endpoint (8 Favours manual
vs strengthening
exercises
116
number of patients 1 RCT (N=134) clinic-based manual 1 year 52% (clinic) and
satisfied with the therapy + follow-up 25% (home)
treatment strengthening exercises p=0.018
vs home-based Favours clinic
Table 56: Use of concomitant medication

Medication use outcome Reference Intervention time Effect size
127
use of rescue 1 RCT (N=66) kinaesthesia + study NS
paracetamol balancing + endpoint (8
vs strengthening
exercises
116
use of concomitant 1 RCT (N=134) clinic-based manual 1 year 48% (clinic) and
medication therapy + follow-up 68% (home)
strengthening exercises p=0.03
vs home-based Favours clinic

128
Osteoarthritis
8.1.8 Evidence statements: manual therapy
Table 57: Pain

Knee osteoarthritis
Manual therapy vs sham ultrasound
29
Pain on movement, VAS 1 RCT , N=140 Manual therapy 12 weeks Manual better than
(change from baseline) (knee taping, post- control: -2.1
mobilisation, treatment (manual) and -1.6
massage + exercise) (control)
vs control (sham
ultrasound)
29
WOMAC Pain (change 1 RCT , N=140 Manual therapy 12 weeks Manual better than
from baseline) (knee taping, post- control
mobilisation, treatment -2.4 (manual) and –
massage + exercise) 2.0 (control)
vs control (sham
ultrasound)
29
Pain severity, KPS 1 RCT , N=140 Manual therapy 12 weeks (end Manual better than
(change from baseline) (knee taping, of treatment control
mobilisation, and 12 weeks 12 weeks: -3.3
massage + exercise) post- (manual) and –2.6
vs control (sham treatment (control)
ultrasound)
12 weeks post-
treatment: -3.1
(manual) and –2.1
(control)
29
Pain frequency, KPS 1 RCT , N=140 Manual therapy 12 weeks (end Manual better than
(change from baseline) (knee taping, of treatment control
mobilisation, and 12 weeks 12 weeks: -4.3
massage + exercise) post- (manual) and –3.0
vs control (sham treatment (control)
ultrasound)
12 weeks post-
treatment: -4.1
(manual) and –2.5
(control)
29
Clinically relevant 1 RCT , N=140 Manual therapy 12 weeks NS
reduction in Pain (≥1.75 (knee taping, post-
cm), VAS mobilisation, treatment
massage + exercise)
vs control (sham
ultrasound
29
Pain on movement, VAS 1 RCT , N=140 Manual therapy 12 weeks (end Both groups similar
(change from baseline) (knee taping, of treatment) -2.2 (manual) and –
mobilisation, 2.0 (control)
massage + exercise)
vs control (sham
ultrasound
29
WOMAC Pain (change 1 RCT , N=140 Manual therapy 12 weeks (end Both groups similar
from baseline) (knee taping, of treatment) -2.1 (manual) and –

129
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mobilisation, 2.0 (control)
massage + exercise)
vs control (sham
ultrasound
Manual therapy vs meloxicam
463
Pain (VAS); Pain 1 , N=60 manual therapy mid- NS
Intensity (NRS-101); (motion palpation, treatment and
Pressure Pain Tolerance, thrust movement, at 3 weeks
PPT (kg/sec) manipulation) vs (end of
meloxicam treatment)
Manual therapy (pre-treatment vs post-treatment)
79
Functional squat Pain 1 cohort study , Manual therapy Immediate p<0.01
(NPRS) N=39 (hip oscillatory Favours manual
mobilizations) –
pre-treatment vs
post-treatment
79
FABER pain (NPRS) 1 cohort study , Manual therapy Immediate p<0.05
N=39 (hip oscillatory Favours manual
mobilizations) –
pre-treatment vs
post-treatment
79
Hip Flexion pain (NPRS) 1 cohort study , Manual therapy Immediate p<0.05
mobilizations) –
pre-treatment vs
post-treatment
79
Hip Scour pain (NPRS) 1 cohort study , Manual therapy Immediate p<0.01
mobilizations) –
pre-treatment vs
post-treatment
Manual therapy vs usual care
353
WOMAC Pain, VAS 1 RCT (N=68) Swedish massage vs 8 weeks (end –23.2mm (manual)
(change from baseline) usual care of treatment) and –3.1mm (usual
care), p<0.001
Favours manual
353
Pain, VAS (change from 1 RCT (N=68) Swedish massage vs 8 weeks (end –22.6mm (manual)
baseline) usual care of treatment) and –2.0mm (usual
care)
Manual better
MANUAL THERAPY vs MANUAL CONTACT

319
Knee PPT 1 RCT (N=38) Manual therapy Immediate 27.3% (manual) and
(Large-amplitutde 6.4% (control),
AP glide) vs control p=0.008
(manual contact) Favours manual
319
Heel PPT 1 RCT (N=38) Manual therapy Immediate 15.3% (manual) and
AP glide) vs control p<0.001

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319
WOMAC pain; Pain 1 RCT (N=38) Manual therapy Immediate NS
during timed ‘up and go’ (Large-amplitutde
test (VAS) AP glide) vs control
(manual contact)
MANUAL THERAPY vs NO CONTACT
319
Knee PPT 1 RCT (N=38) Manual therapy Immediate 27.3% (manual) and
AP glide) vs control p=0.01
(no contact) Favours manual
319
Heel PPT 1 RCT (N=38) Manual therapy Immediate 15.3% (manual) and
319
WOMAC pain; Pain 1 RCT (N=38) Manual therapy Immediate NS
during timed ‘up and go’ (Large-amplitutde
test (VAS) AP glide) vs control
(no contact)
Hip
Manual therapy vs exercise
193
Pain at rest (VAS) 1 RCT , N=109 manual therapy 5 weeks, end Effect size 0.5, 95%
(manipulation + of study CI -16.4 to –1.6,
stretching) vs p<0.05
exercise Favours manual
193
Pain walking (VAS) 1 RCT , N=109 manual therapy 5 weeks, end Effect size 0.5, 95%
Manual therapy (pre- treatment vs post-treatment)
271
Pain (NPRS), change 1 Case-series , manual therapy Between 2-5 mean change -4.7
from baseline N=7 (thrust movement, weeks favours manual
manipulation) pre-
treatment vs post-
treatment
Table 58: Stiffness

Knee osteoarthritis
353
WOMAC Stiffness, VAS 1 RCT (N=68) Swedish massage vs 8 weeks (end –21.6 mm (manual)
(change from baseline) usual care of treatment) and –4.3 mm (usual
care), p<0.007
Favours manual
Hip
193
Starting stiffness (VAS) 1 RCT , N=109 manual therapy 5 weeks, end Effect size 0.5, 95%

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Table 59: Function

Knee osteoarthritis
115
6 minute walk distance 1 RCT , N=83 manual therapy 8 weeks (4 170m difference,
(movements, weeks post- 95% CI 71 to 270 m,
mobilisation and treatment) p<0.05
stretching) +
exercise vs control
(sham ultrasound)
115
WOMAC score 1 RCT , N=83 manual therapy 8 weeks (4 599m difference,
(movements, weeks post- 95% CI 197 to
mobilisation and treatment) 1002m, p<0.05
stretching) +
exercise vs control
(sham ultrasound)
29
Restriction of activity, 1 RCT , N=140 Manual therapy 12 weeks -1.9 (manual) and -
VAS (change from (knee taping, post- 1.7 (control)
baseline) mobilisation, treatment Manual better
massage) + exercise
vs control (sham
ultrasound)
29
WOMAC Physical 1 RCT , N=140 Manual therapy 12 weeks -7.5 (manual) and -
function (change from (knee taping, post- 6.7 (control)
massage) + exercise
vs control (sham
ultrasound)
29
Step test, number of 1 RCT , N=140 Manual therapy 12 weeks 2.1 (manual) and 1.8
steps (change from (knee taping, post- (control)
massage) + exercise
vs control (sham
ultrasound)
29
Quadriceps strength, 1 RCT , N=140 Manual therapy 12 weeks (end 12 weeks: 0.3
N/kg (change from (knee taping, of treatment) (manual) and 0.0
baseline) at 12 weeks mobilisation, and 12 weeks (control)
(end of treatment), 0.3 massage) + exercise post- 12 weeks post-
and 0.0 respectively and vs control (sham treatment treatment: 0.3
at, 0.3 and 0.1 ultrasound) (manual) and 0.1
respectively. (control)
Manual better
29
Step test, number of 1 RCT , N=140 Manual therapy 12 weeks (end 1.5 (manual) and 1.4
steps (change from (knee taping, of treatment) (control)
baseline) mobilisation, Both groups similar

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massage) + exercise
vs control (sham
ultrasound)
29
Restriction of activity, 1 RCT , N=140 Manual therapy 12 weeks (end -1.6 (manual) and -
VAS (change from (knee taping, of treatment) 1.9 (control)
baseline mobilisation, Control better
massage) + exercise
vs control (sham
ultrasound)
29
WOMAC Physical 1 RCT , N=140 Manual therapy 12 weeks (end -7.8 (manual) and –
function (change from (knee taping, of treatment) 8.2 (control)
baseline) mobilisation, Control better
massage) + exercise
vs control (sham
ultrasound)
463
Flexion (degrees); 1 , N=60 manual therapy mid- NS
Extension (degrees) and (motion palpation, treatment and
Patient-Specific thrust movement, at 3 weeks
Functional Scale, PSFS (1- manipulation) vs (end of
11 scale). meloxicam treatment)
Manual therapy vs manual contact

319
Sit-to-stand time 1 RCT (N=38): Manual therapy Immediate -5.06 (manual) and -
(Large-amplitutde 0.35 (control),
319
Total ‘up and go’ time 1 RCT (N=38): Manual therapy Immediate NS
(Large-amplitutde
AP glide) vs control
(manual contact)
Manual therapy vs no contact
319
Sit-to-stand time 1 RCT (N=38): Manual therapy Immediate -5.06 (manual) and -
(Large-amplitutde 7.92 (control),
319
Total ‘up and go’ time 1 RCT (N=38): Manual therapy Immediate NS
(Large-amplitutde
AP glide) vs control
(no contact)
Manual therapy (pre-treatment vs post-treatment)
79
Functional squat ROM 1 cohort study , Manual therapy Immediate p<0.05
(degrees) N=39 (hip oscillatory Favours manual
mobilizations) –
pre-treatment vs
post-treatment
79
Hip Flexion ROM 1 cohort study , Manual therapy Immediate p<0.01
(degrees) N=39 (hip oscillatory Favours manual
mobilizations) –
pre-treatment vs
post-treatment

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79
FABER ROM (degrees), 1 cohort study , Manual therapy Immediate +3.6
change from baseline N=39 (hip oscillatory Favours manual
mobilizations) –
pre-treatment vs
post-treatment
353
WOMAC total, VAS 1 RCT (N=68) Swedish massage 8 weeks (end –21.2mm (manual)
(change from baseline) vs usual care of treatment) and –4.6mm
(control), p<0.001
Favours manual
353
WOMAC Physical 1 RCT (N=68) Swedish massage 8 weeks (end –20.5 mm (manual)
functional disability, VAS vs usual care of treatment) and –0.02 mm
(change from baseline (control), p=0.002
Favours manual
353
ROM, degrees (change 1 RCT (N=68) Swedish massage 8 weeks (end 7.2 (manual) and –
from baseline vs usual care of treatment) 1.1 mm (control),
Manual better
353
1 RCT (N=68) Swedish massage 8 weeks (end -1.8 (manual) and
50-foot walk time, secs vs usual care of treatment) 0.2 (control),
(change from baseline Manual better
Hip
193
Walking speed (secs) 1 RCT , N=109 manual therapy 5 weeks, end Effect size 0.3, 95%
193
ROM flexion-extension 1 RCT , N=109 manual therapy 5 weeks, end Effect size 1.0, 95%
(degrees) (manipulation + of study CI 8.1 to 22.6,
193
ROM external-internal 1 RCT , N=109 manual therapy 5 weeks, end Effect size 0.9, 95%
rotation (degrees) (manipulation + of study CI 6.1 to 17.3,
193
ROM flexion-extension 1 RCT , N=109 manual therapy 5 weeks, end Effect size 1.0, 95%
(degrees) (manipulation + of study CI 8.1 to 22.6,
Manual therapy (pre- treatment vs post-treatment)
271
Passive ROM (degrees) 1 Case-series , manual therapy 2 to 5 weeks mean change +23.3
N=7 (thrust movement, Favours manual
manipulation) pre-
treatment vs post-
treatment
271
Passive ROM internal 1 Case-series , manual therapy 2 to 5 weeks mean change +16.3
rotation (degrees) N=7 (thrust movement, Favours manual
manipulation) pre-
treatment vs post-
treatment

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271
Total Hip Pasive ROM 1 Case-series , manual therapy 2 to 5 weeks mean change +84.3
(degrees) N=7 (thrust movement, Favours manual
manipulation) pre-
treatment vs post-
treatment
271
Disability (Harris Hip 1 Case-series , manual therapy 2 to 5 weeks mean change +20.0
Score) N=7 (thrust movement, Favours manual
manipulation) pre-
treatment vs post-
treatment
Table 60: Global assessment

Global assessment Assessment Outcome / Effect
Knee osteoarthritis
29
Patient global 1 RCT , N=140 Manual therapy 12 weeks NS
assessment of (knee taping, post-
improvement mobilisation, treatment
massage) + exercise
vs control (sham
ultrasound)
Hip
193
Main complaint 1 RCT , N=109 manual therapy 5 weeks, end Effect size 0.5, 95%
(manipulation + of study CI -20.4 to -2.7
stretching) vs Favours manual
exercise
193
Improvement of the 1 RCT , N=109 manual therapy 5 weeks, end 81% and 50%
main complaint at 5 (manipulation + of study respectively; OR
weeks, end of study stretching) vs 1.92, 95% CI 1.30 to
exercise 2.60
Favours manual
193
Worsening of the main 1 RCT , N=109 manual therapy 5 weeks, end 19% and 50%
complaint at 5 weeks, (manipulation + of study Favours manual
end of study stretching) vs
exercise

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Knee osteoarthritis
29
SF-36 Bodily Pain 1 RCT , N=140 Manual therapy 12 weeks (end 12 weeks: -11.4
(change from baseline) (knee taping, of treatment) (manual) and –9.4
mobilisation, and 12 weeks (control)
massage) + exercise post- 12 weeks post-
vs control (sham treatment treatment: -6.7
ultrasound) (manual) and –4.9
(control)
Manual better
29
SF-36 Physical function 1 RCT , N=140 Manual therapy 12 weeks (end 12 weeks: -12.2
(change from baseline) (knee taping, of treatment) (manual) and –7.9
vs control (sham treatment treatment: -9.7
ultrasound) (manual) and –5.4
(control)
Manual better
29
SF-36 Physical role 1 RCT , N=140 Manual therapy 12 weeks -13.3 (manual) and -
(change from baseline) (knee taping, post- 11.8 (control)
mobilisation, treatment Manual better
massage) + exercise
vs control (sham
ultrasound)
29
AQoL (change from 1 RCT , N=140 Manual therapy 12 weeks 0.07 (manual) and
baseline) (knee taping, post- 0.001 (control)
mobilisation, treatment Manual better
massage) + exercise
vs control (sham
ultrasound)
29
AQoL (change from 1 RCT , N=140 Manual therapy 12 weeks (end 0.05 (manual) and
baseline) (knee taping, of treatment) 0.04 (control)
mobilisation, Both groups similar
massage) + exercise
vs control (sham
ultrasound)
29
SF-36 Physical role 1 RCT , N=140 Manual therapy 12 weeks (end 14.8 (manual) and
(change from baseline) (knee taping, of treatment) 16.0 (control)
mobilisation, Control better
massage) + exercise
vs control (sham
ultrasound)
Hip
193
SF-36 role physical 1 RCT , N=109 manual therapy 5 weeks, end Effect size 0.4, 95%
function (manipulation + of study CI -21.5 to -1.1,
193
SF-36 bodily pain and 1 RCT , N=109 manual therapy 5 weeks, end NS
physical function (manipulation + of study

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stretching) vs
exercise
Table 62: Adverse Events

AEs outcome Reference Intervention time size
Knee osteoarthritis
29
Number of patients with 1 RCT , N=140 Manual therapy 12 weeks (end Control better
AEs (knee taping, of treatment)
mobilisation,
massage) + exercise
vs control (sham
ultrasound)
463
Number of AEs (N=0, 0% 1 RCT , N=60 manual therapy 3 weeks (end 0% (manual) and
and N=3, 10% (motion palpation, of treatment) 10% (meloxicam)
respectively). thrust movement, Manual better
manipulation) vs
meloxicam
Table 63: Study withdrawals

Withdrawals outcome Reference Intervention time size
Knee osteoarthritis
29
Number of withdrawals 1 RCT , N=140 Manual therapy 12 weeks (end 12 weeks: 18%
(knee taping, of treatment) (manual) and 3%
vs control (sham treatment treatment: 23%
ultrasound) (manual) and 6%
(control)
Control better
115
Number of withdrawals 1 RCT , N=83 manual therapy 4 weeks (end 12% (manual) and
(movements, of treatment) 21% (control)
mobilisation and Manual better
stretching) +
exercise vs control
(sham ultrasound)
Hip
193
Number of withdrawals 1 RCT , N=109 manual therapy end of study N=15 (manual) and
+ number lost to follow- (manipulation + (week 5) and 6 N=13 (exercise)
up stretching) vs months (5 Both groups similar
exercise months post-
intervention)

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193
Withdrawals due to AEs, 1 RCT , N=109 manual therapy end of study N=3 (manual) and
increase of complaints (manipulation + (week 5) N=2 (exercise)
stretching) vs Both groups similar
exercise
8.1.9 Health economic evidence overview

We looked at studies that focused on economically evaluating exercise programmes compared to
other exercise interventions, or to no treatment/placebo for the treatment of adults with
Osteoarthritis. Thirteen studies were identified through the literature search as possible cost
effectiveness analyses in this area. On closer inspection nine of these studies
56,80,145,204,207,239,284,291,342,473
were excluded for:
 not directly answering the question;
 not including sufficient cost data to be considered a true economic analyses;
 involving a study population of less than 30 people.
Four papers were found to be methodologically sound and were included as health economics
evidence. After the re-run search, 2 more papers were included as health economic evidence.
One recent UK study involved a full pragmatic, single-blind randomized clinical trial accompanied by
a full economic evaluation 291. The study duration was 1 year, and the study population included 214
patients meeting the American College of Rheumatology’s classification of knee OA, selected from
referrals from the primary and secondary care settings. The interventions considered were:
 Group 1: A home exercise programme aimed at increasing lower-limb strength, and endurance,
and improving balance.
 Group 2: The second group was supplemented with 8 weeks of twice-weekly knee classes run by
a physiotherapist. Classes represented typical knee class provision in the UK.
Effectiveness data was taken from the accompanying RCT. An NHS perspective was taken meaning
that costs included resource use gathered from patient records and questionnaires, the cost of the
intervention estimated from resource use data and national payscale figures, capital and overhead
costs, and one-off expenses incurred by the patient. Travel costs were considered in sensitivity
analysis. QALYs were calculated through converting EQ-5D scores obtained at baseline, 1, 6, and 12
months in to utilities.
One recent UK study 447 conducted a cost effectiveness analysis of exercise, telephone support, and
no intervention. The study duration was 2 years and the study population involved adults aged over
45-years reporting current knee pain (exclusion criteria included having had a total knee
replacement, lower limb amputation, cardiac pacemaker, unable to give informed consent, or no
current knee pain). The intervention groups were:
 Exercise therapy. This included quadriceps strengthening, aerobic exercise taught in a graded
program, and resistance exercises using a rubber exercise band. A research nurse taught the
program in the participants’ homes. The initial training phase consisted of 4 visits lasting ~30
minutes in the first 2 months, with follow-up visits scheduled every 6 months thereafter.
Participants were encouraged to perform the program daily, taking 20-30 minutes.
 Monthly telephone support. This was used to monitor symptoms and to offer simple advice on
the management of knee pain. This aimed to control for the psychological impact of the exercise
program.
 Combination of exercise and telephone support.

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 No intervention. Patients in this group received no contact between the biannual assessment
visits.
Effectiveness data was obtained from an accompanying RCT (786 participants). Health provider and
patient perspectives are considered regarding costs, however patient specific costs were only
considered in terms of time, and a monetary cost was not placed on this. This means that costs
reported are those relevant for the health provider perspective (direct treatment costs, medical
costs).
A limitation of the study is that it does not distinguish between medical costs incurred due to knee
pain and medical costs incurred due to any other type of illness. This may bias results because
changes in costs may not reflect changes in costs associated with knee pain.
One US study 414 conducted an economic analysis comparing exercise interventions and an education
intervention. The study was 18 months long and focused on people aged 60 or over who have pain
on most days of the month in one or both knees; who have difficulty with one of a variety of
everyday activities; radiographic evidence of knee OA in the tibial-femoral compartments on the
painful knee(s) as judged by a radiologist. The interventions included were:
 Aerobic exercise program = 3-month facility-based program and a 15-month home-based
program. At each session exercise lasted 60 minutes including warm-up, stimulus, and cool-down
phases. Exercise was prescribed three times per week. During the three-month period training
was under the supervision of a trained exercise leader. Between 4 and 6 months participants
were instructed to continue exercise at home and were contacted bi-weekly by the program
leader who made 4 home visits and 6 telephone follow-up calls to participants. For months 7-9
telephone contact was made every 3 weeks, and during months 10-18 monthly follow-up
telephone calls were made.
 Resistance exercise program = 3-month facility based, 15 month home-based. Duration of
session, the number, timing, and type of follow-up was consistent with the aerobic exercise.
Weights were used.
 Health education = this was used as a control to minimize attention and social interaction bias.
During months 1-3 participants received a monthly 1.5 hr educational session, and during months
4-18 participants were regularly contacted by a nurse to discuss the status of their arthritis and
any problems with medications. Telephone contacts were bi-weekly during months 4-6, and
monthly for months 7-18.
Effectiveness data was from the single-blind Fitness and Arthritis in Seniors Trial (FAST) RCT. A health
care payer perspective was adopted. Limitations of the study include that it only reported results
comparing each exercise programme individually with the education control, rather than also
comparing the exercise programmes to one another. Also Incremental Cost Effectiveness Ratios
(ICERs) were calculated incorrectly.
An Australian study 413 economically evaluated a number of different interventions for the treatment
of OA. The population considered varies for the different comparisons. The interventions
considered were:
 Comprehensive mass media program for weight loss
 Intensive primary care weight loss program delivered by GP or dietician for overweight or obese
 Intensive primary care weight loss program delivered by GP or dietician for overweight or obese
with previous knee injury
 Surgery for obese people
 Lay-led group education
 Primary care: GP or clinical nurse educator plus phone support
 Exercise/strength training

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 Home-based basic
 Home-based intensive
 Clinic-based primary care
 Clinic based outpatients
 Specially fitted knee brace
 Non-specific NSAIDs (naproxen, diclofenac)
 COX2s (celecoxib)
 Glucosamine sulfate
 Avocado
 Topical capsaicin /soy unsaponifiable
 Total knee replacement
 Total hip replacement
 Knee arthroscopy with lavage
The paper required published outcomes and costs of the considered interventions to be found. At a
minimum the papers used had to include a precise program description and quantitative evidence of
effectiveness derived from an acceptable research design and preferably health endpoints, a usual
care or placebo control, and a suitable follow-up period. Costs included resources applied to the
intervention and to the management of treatment side effects, and for primary prevention estimated
savings in ‘downstream’ health care service use. Intervention costs were calculated as the product of
program inputs multiplied by current published unit costs.
The paper is limited with regards to its technique applied to compare health outcomes. A ‘transfer to
utility’ (TTU) technique was used which has been criticised in the literature.477 This involves
transforming health outcome scores found in the original trials into quality adjusted life year (QALY)
scores.
One study from the Netherlands investigated behavioural graded activity and usual physiotherapy
treatment for 200 patients with osteoarthritis of the hip or knee.89
The behavioural graded activity group received a treatment integrating the concepts of operant
conditioning with exercise treatment comprising booster sessions. Graded activity was directed at
increasing the level of activity in a time-contingent manner, with the goal of integrating these
activities in the daily lives of patients. Treatment consisted of a 12 week period with a maximum of
18 sessions, followed by 5 preset booster moments with a maximum of 7 sessions (in weeks 18, 25,
34, 42 and 55).
The usual care group received treatment according to the Dutch physio guideline for patients with
OA of hip and/ or knee. This recommends provision of information and advice, exercise treatment
and encouragement of coping positively with the complaints. Treatment consisted of a 12 week
period with a maximum of 18 sessions and could be discontinued within this 12 weeks period if,
according to the physio, all treatment goals had been achieved.
8.1.10 Health economic evidence statements
Home-based exercise Vs Home-based exercise supplemented with class-based exercise
One UK study291 conducted an economic analysis into the effects on supplementing a home-based
exercise programme with a class-based programme.

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Osteoarthritis
Table 64: McCarthy’s cost-benefit estimates

Intervention QALYs gained Cost (1999/00 £)
Home-based 0.022 £445.52
Class-based 0.045 £440.04
These results show that the class-based supplement dominates the home-based intervention alone.
However neither the cost or the effect data were statistically significantly different, so cost
effectiveness acceptability curves (CEACs) were presented. These showed that for all plausible
threshold WTP values the class-based regime was more likely to be cost effective than the home-
based regime. The CEAC showed that the probability of the class-based programme being cost-
saving was just over 50%. At a WTP of £30,000 the probability of the class-based programme being
cost effective was over 70%.
Additional sensitivity analysis was undertaken. When considering only patients for whom complete
cost data was available (n=74, 30 in home-based and 44 in class-based) the class-based group had a
higher probability of being cost effective (approximately 95% at WTP £20,000 to £30,000). Sensitivity
analysis also included adding travel costs to the class-based regime. In this case the class-based
programme was still likely (65% probability) to be cost effective compared to the home-based
programme with a WTP threshold per additional QALY of £20,000-£30,000. There is considerable
uncertainty however with a probability of 30-35% that the class-based programme will not be cost-
effective.
It should be noted that as a one-year time horizon is used, the results are biased against the more
effective intervention, or the intervention for which benefits are likely to be prolonged the most.
This is because these patients will benefit from an increased QALY score for some time going into the
future, assuming that the QALY improvement does not disappear immediately after the intervention
is stopped.
In conclusion, it is likely that supplementing a home-based exercise programme with a class-based

programme will be cost saving or cost effective and will improve outcomes. If travel costs are
included this becomes less likely but it is probable that the class-based supplement will remain cost
effective.
Exercise vs No Exercise vs Telephone
One 2005 UK study447 compared exercise interventions, no treatment, and telephone interventions,
essentially from the health care provider perspective. All costs were reported in pound sterling at
1996 prices.
Table 65: Thomas’s cost-benefit estimates

% of patients showing a 50%
Intervention improvement in knee pain Bootstrapped total costs (95% CI)
Exercise intervention (Exercise, 27% 1,354 (1,350 to 1,358)
Exercise + Telephone, Exercise +
Telephone + Placebo)
No-exercise control (Telephone, 20% (p=0.1) 1,129 (1,125 to 1,132)
Placebo, No intervention)
Non-parametric bootstrapping involves taking samples from the original data multiple times (from both intervention and
control group) to build an empirical estimate. In this paper a sampling distribution of the cost was estimated using this
method.
It should be noted that this paper has a bias against the exercise intervention if it is assumed that the
benefits of the exercise programme continue for some time after the intervention has been stopped.
This is because the intervention would no longer be paid for but some of the benefits may remain.

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Osteoarthritis
There is no evidence of telephone interventions being more effective than no-telephone

interventions, so it is unclear whether adding telephone contact would be cost-effective.
Home-based exercise vs Clinic-based exercise vs Control
An Australian study413 undertakes an economic analysis of a number of different interventions for the
treatment of OA, using a ‘transfer-to-utility’ technique which allows each intervention to be analysed
with regards to their cost per QALY gain.
Table 66: Segal’s cost-effectiveness estimates

Mean program cost Cost/QALY
per person best estimate
Mean QALY gain (2003Aus$, vs control (no
Intervention per person converted to 2003 £) intervention) ICER
Home-based 0.022 $400 (£164) $18,000 Extendedly
exercise – basic (£7,377) to dominated
equivocal
Clinic-based exercise 0.091 $480 (£197) $5,000 (£2,049) $5,000 (£2,049)
– primary care
Clinic-based exercise 0.078 $590 (£242) $8,000 (£3,279) Dominated
– outpatients
Home-based 0.100 $1,420 (£582) $15,000 $104,444 (£42,805)
exercise – intensive (£6,148)
Note that the effectiveness data these estimates are based on were generally from studies of around
12 weeks, but these estimates calculate costs and QALYs for a one year time period – ie as if the
intervention was continued for one full year.
Compared to one another clinic-based exercise in a primary care setting [between one and three 30
minute exercise sessions per week for 12 weeks given on an individual basis by a physiotherapist,
which included strengthening and lengthening exercises for muscle functions, mobility, coordination,
and elementary movement plus locomotion abilities] is cost effective if there is a WTP per additional
QALY gained of between approximately £2,049 and £42,805. For a WTP higher than £42,805 the
evidence suggests that intensive home-based exercise may be cost effective. Home-based basic
exercise is extendedly dominated by clinic-based exercise in primary care. Clinic-based exercise in an
outpatient setting is dominated by clinic-based exercise in primary care.
Aerobic exercise versus resistance exercise versus education control
One US study414 considers the cost effectiveness of aerobic exercise and resistance exercise
compared to an education control from the health care payer perspective.
Table 67: Sevick’s cost-effectiveness estimates

Aerobic Resistance
Education exercise exercise Cost effectiveness
Cost per participant (1994 $343.98 $323.55 $325.20 Aerobic cheaper
US$)
Self reported disability 1.90 1.72 1.74 Aerobic dominant
score (points)
6-min walking distance 1,349 1,507 1,406 Aerobic dominant
(feet)
Stair climb (secs) 13.9 12.7 13.2 Aerobic dominant

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Aerobic Resistance
Education exercise exercise Cost effectiveness
Lifting and carrying task 10.0 9.1 9.3 Aerobic dominant
(secs)
Car task (secs) 10.6 8.7 9.0 Aerobic dominant
Transfer pain frequency 3.18 2.89 2.99 Aerobic dominant
(points)
Ambulatory pain frequency 3.46 3.12 3.06 Resistance CE if WTP
(points) $27.5 per additional
point
Transfer pain intensity 2.28 2.10 2.11 Aerobic dominant
(points)
Ambulatory pain intensity 2.45 2.27 2.34 Aerobic dominant
(points)
Note that the resistance and aerobic exercise programmes were undertaken in the same setting ie 3
months facility-based and 15 months home-based and cost differences were only from medical
referrals and adverse events, despite the fact that weights were used in the resistance exercise
group. The authors state that the educational control arm of the study would be equivalent to a ‘no
special instruction’ group in the real world. They state that the cost for this would be zero, but that it
is possible outcomes would be slightly worse for these patients.
Also, similarly to other studies with relatively short time horizons, and which stop recording outputs
as soon as the intervention is stopped, this paper may bias against the intervention as the benefits of
the intervention may not disappear as soon as the intervention is discontinued.
In conclusion, aerobic exercise has been shown to result in lower costs than a resistance exercise
group and an educational control group in the US, while incurring lower medical costs. Exercise
programmes are likely to be cost effective compared to an educational programme involving regular
telephone follow-up with patients.
The study89 found that the behavioural graded activity group was less costly than the usual care
group, but not statistically significantly so. It is notable that more joint replacement operations took
place in the usual care group, and it is unclear whether this is related to the interventions under
consideration. The difference in effect of the two treatments was minimal for all outcomes. The
study was excluded from the clinical review for this guideline, and given the uncertainty in the results
no evidence statements can be made based upon it.
A recent UK study which is soon to be published investigates the Enabling Self-management and
Coping with Arthritic knee Pain through Exercise (ESCAPE-knee pain) programme in 418 patients with
chronic knee pain (Hurley ref). The interventions studied were:
 Usual primary care
 Usual primary care plus individual rehabilitation (Indiv-ESCAPE)
 Usual primary care plus rehabilitation in groups of about 8 participants (Grp-ESCAPE).
The content and format of ESCAPE was the same for the individual and group patients. They
consisted of 12 sessions (twice weekly for 6 weeks) involving self-management advice and exercises
to improve lower limb function.
The results of the study suggest that the group patients achieved very similar results as the individual
patients, but the group costs were less. The probability that ESCAPE (Indiv and Grp combined) is cost
effective compared to usual care based on QALYs, with £20,000 willingness to pay threshold for an
additional QALY = 60%

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The Probability that ESCAPE (Indiv and Grp combined) is cost effective compared to usual care based
on 15% improvement in WOMAC function, with £1,900 willingness to pay threshold for an additional
person with a 15% improvement = 90%. With a willingness to pay threshold of £800 the probability
is 50%. Based on the WOMAC outcome, the probability of Indiv-ESCAPE being more cost effective
than Grp-ESCAPE reached 50% at willingness to pay threshold of £6,000.
Exercise
The GDG recognised the need to distinguish between exercise therapy aimed at individual joints and
general activity-related fitness. Evidence from a large well conducted systematic review385 and one
large randomised controlled trial312 for knee osteoarthritis demonstrated the beneficial effects of
exercise compared with no exercise. Exercise in this context included aerobic walking, home
quadriceps exercise, strengthening and home exercise, aerobic exercise with weight training, and
diet with aerobic and resisted exercise. Exercise reduced pain, disability, medication intake and
improved physical functioning, stair climbing, walking distance, muscle strength, balance, self-
efficacy and mental health and physical functioning (SF-36). The majority of these beneficial
outcomes were seen at 18 months.
The strengths of these effects were not evident for hip and hand osteoarthritis. However, there is
limited evidence for hip and hand osteoarthritis and the mechanisms of exercise on the hip and hand
may be different to those for knee osteoarthritis.159
There is limited evidence for the benefits of one type of exercise over another but delivery of
exercise in a class setting supplemented by home exercise may be superior to home exercise alone in
terms of pain reduction, improved disability and increased walking speed.292 Classes were also
shown to be cost effective. A class based exercise programme was superior to a home exercise alone
programme at 12 months for pain, disability and walking speed in knee osteoarthritis.291 This study
was conducted in a secondary care setting and patients were referred from primary and secondary
care.
There is limited evidence to suggest exercise in water may be beneficial in the short term. There is
difficulty in interpreting the study findings (one in pool based sessions in the community in the UK, a
second of hydrotherapy in the US) for current practice in the NHS.
Exercise therapies given by health professionals to people and to groups of patients (e.g. exercise
classes) may both be effective and locally available. Individual patient preferences can inform the
design of exercise programmes.
Adverse events were not consistently studied, but the risk of adverse events is considered low if the
suitability of the exercise for the individual is appropriately assessed by a trained health professional.
The GDG considered that the choice between individual and group exercise interventions has to be
informed by patient preference, and tailoring it to the individual will achieve longer-term positive
behavioural change.
The GDG also considered adding reference to the Expert Patient Programme but NICE guidelines do
not specify the service model used to deliver effective interventions, and therefore an open
recommendation is made focussing on the intervention shown to be of benefit.
Manual therapy
The majority of studies evaluated manual therapy for osteoarthritis in combination with other
treatment approaches, for example exercise. This reflected current practice in physiotherapy, where

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Osteoarthritis
manual therapy would not be used as a sole treatment for osteoarthritis but as part of a package of
care.
There was strong evidence for the benefit of manual therapy alone compared with exercise.193 Again
the design of this study reflects usual physiotherapy practice, where there is limited evidence for the
benefit of exercise for hip osteoarthritis. The exercise programme was based on that reported by van
Barr et al.469 Manual therapy included stretching techniques of the identified shortened muscles
around the hip joint and manual traction which was repeated at each visit until the therapist
concluded optimal results. Patients were treated twice weekly for 5 weeks with a total of 9
treatments. The duration of this programme is somewhat longer than that usually available in the
NHS, however, the benefit of the manual therapy would indicate that such a programme should be
considered in people who are not benefiting from home stretching exercises.
There have been few reported adverse events of manual therapy, pain on massage being one.
12.Advise people with osteoarthritis to exercise as a core treatment (see recommendation 6),
irrespective of age, comorbidity, pain severity or disability. Exercise should include:
 local muscle strengthening and
 general aerobic fitness.
It has not been specified whether exercise should be provided by the NHS or whether the
healthcare professional should provide advice and encouragement to the person to obtain and
carry out the intervention themselves. Exercise has been found to be beneficial but the clinician
needs to make a judgement in each case on how to effectively ensure participation. This will
depend upon the person's individual needs, circumstances and self-motivation, and the
availability of local facilities. [2008]
13.Manipulation and stretching should be considered as an adjunct to core treatments, particularly

for osteoarthritis of the hip. [2008]
8.2 Weight loss

Excess or abnormal mechanical loading of the joint appears to be one of the main factors leading to
the development and progression of osteoarthritis. This is apparent in secondary forms of
osteoarthritis, such as that related to developmental dysplasia of the hip. It also occurs in primary
osteoarthritis, where abnormal or excess loading may be related to obesity or even relatively minor
degrees of mal-alignment (varus or valgus deformity) at the knee.
The association of obesity with the development and progression of osteoarthritis, especially at the
knee, provides the justification for weight reduction. Weight loss is usually achieved with either
dietary manipulation and/or exercise, where the independent effect of the latter must also be
considered.

We looked for studies that investigated the efficacy and safety of weight loss versus no weight loss
with respect to symptoms, function and quality of life in adults with osteoarthritis. One systematic
review and meta-analysis75 and 4 additional RCTs197,311,379,450 were found. One of these RCTs379 was a

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subgroup analysis of another trial304. 3 RCTs197,311,450 were excluded due to methodological

limitations. No relevant cohort or case-control studies were found.
The systematic review and meta-analysis75 on weight loss versus no weight loss in patients with knee
osteoarthritis. The MA included 5 RCTs (with N=454 participants). All RCTs were methodologically
sound. Studies included in the analysis differed with respect to:
 Intervention – weight loss method (4 RCTs exercise and cognitive-behavioural therapy; 1 RCT low-
energy diet; 1 RCT Mazindol-weight loss drug + low-energy diet).
 Study size and length.
The one RCT379 not included in the systematic review was methodologically sound and compared
weight loss (exercise vs diet vs exercise + diet) vs no weight loss (healthy lifestyle education)in N=316
patients with knee osteoarthritis in an 18-month treatment phase.
Table 68: Pain

Knee osteoarthritis
Weight loss vs no weight loss
75
Pain 1MA 4 RCTs, weight loss vs no Between 8 NS
N=417 weight loss weeks to 18
months
75
Predictors of 1MA 4 RCTs, weight loss vs no Between 8 Not predictors
significant change in N=417 weight loss weeks to 18
pain score -Body months
weight change (%) or
rate of weight change
per week
Table 69: Function

Knee osteoarthritis
Weight loss vs no weight loss
75
Self-reported 1MA 4 RCTs, weight loss vs no Between 8 weight loss 6.1 kg;
disability N=417 weight loss weeks to 18 effect size 0.23,
months 95% CI 0.04 to 0.42,
p=0.02
Favours weight loss
75
Lequesne’s Index 1MA 2 RCTs, weight loss vs no 6 to 8 weeks NS
N=117 weight loss
75
Predictors of 1MA 4 RCTs, weight loss vs no Between 8 Predictor
significant reduction N=417 weight loss weeks to 18
in self-reported months
disability - Body
weight change
(weight reduction of
at least 5.1%)
75
Predictors of 1MA 4 RCTs, weight loss vs no Between 8 Not predictor

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significant reduction N=417 weight loss weeks to 18
in self-reported months
disability - weight
change per week (at
least 0.24%)
Table 70: Function

Knee osteoarthritis
Weight loss vs minimal weight loss
379
SF-36 dimensions of 1 RCT , N=316 weight loss (diet) 18-months (end NS
composite mental vs minimal weight of treatment)
health, composite loss (healthy
physical health score, lifestyle)
patient satisfaction
with function, body
pain, physical role,
general health, social
functioning, vitality,
emotional role
379
SF-36 patient 1 RCT , N=316 weight loss 18-months (end p<0.01
satisfaction with (exercise) vs of treatment) Favours weight loss
function minimal weight
loss (healthy
lifestyle)
379
SF-36 dimensions 1 RCT , N=316 weight loss 18-months (end NS
composite mental (exercise) vs of treatment)
health, composite minimal weight
physical health score, loss (healthy
body pain, Physical lifestyle)
role, general health,
social functioning,
vitality, emotional
role
379
SF-36 dimensions of 1 RCT , N=316 weight loss (diet + 18-months (end All: p< 0.01
composite physical exercise) vs of treatment) Favours weight loss
health score, patient minimal weight
satisfaction with loss (healthy
function, physical lifestyle)
role, general health,
social functioning
379
SF-36 dimensions of 1 RCT , N=316 weight loss (diet + 18-months (end NS
composite mental exercise) vs of treatment)
health, vitality and minimal weight
emotional role loss (healthy
lifestyle)
Weight loss vs weight loss
379
SF-36 patient 1 RCT , N=316 Weight loss (diet + 18-months (end P<0.01
satisfaction with exercise) vs weight of treatment) Favours diet +

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function loss (diet) exercise
379
SF-36 body pain 1 RCT , N=316 Weight loss (diet + 18-months (end P<0.01
exercise) vs weight of treatment) Favours diet +
loss (exercise) exercise
Table 71: Weight loss

Weight loss outcome Reference Intervention time size
Knee osteoarthritis
379
Weight loss (%) 1 RCT , N=316 weight loss (diet vs 18 months Diet (5.7%), diet +
exercise vs diet + (end of exercise (4.4%),
exercise) vs treatment) exercise (2.6%),
control, minimal control - healthy
weight loss lifestyle (1.3%).
(healthy lifestyle)

Published data suggest that interventions reducing excess load, including weight loss, lead to
improvement in function, providing the magnitude of weight loss is sufficient. In contrast, the effect
of weight loss on pain is inconsistent. The only study to show an unequivocal effect on WOMAC pain
as a primary outcome measure included exercise as part of the intervention304. Other studies suggest
exercise might achieve this outcome in the absence of weight loss (see 7.1), although the exercise
alone arm in this study did not achieve a statistically significant reduction in pain.
Furthermore, there is no clear evidence so far that weight loss, either alone or in combination with
exercise, can slow disease progression. Although only one of the studies reviewed specifically
addressed this question304, it was small (N=84), of relatively short duration and therefore
underpowered for this outcome. Nor is there a definite threshold of weight below which the
beneficial effect of weight loss on function is reduced or diminished, although all of the studies were
restricted to those who were overweight (BMI>26.4 kg.m-2). Also, all of the studies have been
conducted in knee osteoarthritis, with consequent difficulties in generalising the results to other
joints, where mechanical influence may be less. The other health benefits of sustained weight loss
are generally assumed to justify its widespread recommendation, but there is a paucity of trials
showing that the kind of sustainable weight loss which would achieve metabolic and cardiovascular
health benefits is achievable in clinical practice. The NICE guideline for obesity provides information
on this evidence and the most effective weight loss strategies323.
Despite the limitations of the available evidence, the benefits of weight loss in people with
osteoarthritis who are overweight are generally perceived to be greater than the risks. The GDG
therefore advocate weight loss in all obese and overweight adults with osteoarthritis of the knee and
hip who have associated functional limitations.
14.Offer interventions to achieve weight losse as a core treatment (see recommendation 6) for
people who are obese or overweight. [2008]
e
See Obesity: guidance on the prevention, identification, assessment and management of overweight and obesity in adults
and children (NICE clinical guideline 43).

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8.3 Electrotherapy
Electrotherapy and electrophysical agents include pulsed short-wave therapy (pulsed
electromagnetic energy, PEME), interferential therapy, laser, Transcutaneous Electrical Nerve
Stimulation (TENS) and ultrasound. All are commonly used to treat the signs and symptoms of OA
such as pain, trigger point tenderness and swelling. These modalities involve the introduction of
energy into affected tissue resulting in physical changes in the tissue as a result of thermal and non-
thermal effects.
Ultrasound
The therapeutic effects of ultrasound have been classifed as relating to thermal and non-thermal
effects132. Thermal effects cause a rise in temperature in the tissue and non- thermal effects
(cavitation, acoustic streaming) can alter the permeability of the cell membrane20,445 which is thought
to produce therapeutic benefits512. The potential therapeutic benefits seen in clinical practice may be
more likely in tissue which has a high collagen content, for example a joint capsule rather than
cartilage and bone which have a lower collagen content.
Pulsed shortwave therapy (Pulsed electromagnetic energy, PEME)
Pulsed short wave therapy has been purported to work by increasing blood flow, facilitating the
resolution of inflammation and increasing deep collagen extensibility411. The application of this type
of therapy can also produce thermal and non-thermal effects. The specific effect may be determined
by the specific dose.
Transcutaneous Electrical Nerve Stimulation or TENS (also termed TNS)
TENS produces selected pulsed currents which are delivered cutaneously via electrode placement on
the skin. These currents can activate specific nerve fibres potentially producing analgesic
responses67,70. TENS is recognised as a treatment modality with minimal contraindications480. The
term AL-TENS is not commonly used in the UK. It involves switching between high and low frequency
electrical stimulation and many TENS machines now do this. The term is more specific to stimulating
acupuncture points.
Interferential therapy
Interferential therapy can be described as the transcutaneous application of alternating medium-

frequency electrical currents, and may be considered a form of TENS. Interferential therapy may be
useful in pain relief, promoting healing and producing muscular contraction282.
Laser
Laser is an acronym for Light Amplification by the Stimulated Emission of Radiation. Therapeutic
applications of low intensity or low level laser therapy at doses considered too low to effect any
detectable heating of the tissue, have been applied to treat musculoskeletal injury24.

We looked for studies that investigated the efficacy and safety of electrotherapy (ultrasound, laser,
transcutaneous electrical nerve stimulation [TENS, TNS, AL-TENS], pulsed shortwave diathermy,
interferential therapy) versus no treatment, placebo or other interventions with respect to
symptoms, function, and quality of life in adults with osteoarthritis. Five systematic reviews and

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Osteoarthritis
meta-analyses47,206,290,337,384 were found on electrotherapy (laser, electromagnetic fields, ultrasounds

and TENS) and 6 additional RCTs23,68,69,339,442,508 on electrotherapy (laser, electromagnetic fields and
TENS). Due to the large volume of evidence, trials with a sample size N < 40 were excluded.
The meta-analyses assessed the RCTs for quality and pooled together data for the outcomes of
symptoms and function. However, the outcomes of quality of life and adverse events (AEs) were not
always reported. Results for quality of life have been taken from the individual RCTs included in this
systematic review.
Ultrasound
One SR/MA384 was found on ultrasound in patients with knee or hip osteoarthritis. The MA included
3 RCTs (with N=294 participants) on comparisons between therapeutic ultrasound (continuous or
pulsed) versus placebo or galvanic current or shorth wave diathermy (SWD). All RCTs were
randomised and of parallel group design. Studies included in the analysis differed with respect to:
 Comparison used (1 RCT placebo – sham ultrasound; 1 RCT short wave diathermy; 1 RCT galvanic
current)
 Treatment regimen (stimulation frequency and intensity; placement of electrodes; lengths of
stimulation time and how often TENS was applied)
 Trial size, blinding, length, follow-up and quality.
Laser
One SR/MA47 and 2 RCTs442,508 were found that focused on laser therapy.
The MA47 included 7 RCTs (with N=345 participants) on comparisons between laser therapy versus
placebo in patients with osteoarthritis. All RCTs were randomised, double-blind and parallel group
studies. Studies included in the analysis differed with respect to:
 Site of osteoarthritis (4 RCTs knee, 1 RCT thumb, 1 RCT hand, 1 RCT not specified)
 Type of laser used (2 RCTs He-Ne laser of 632.8 nm; 1 RCT space laser 904 nm; 4 RCTs Galenium-
Arsenide laser – either 830 or 860 nm)
 Treatment regimen (4 RCTs 2-3 sessions/week; 1 RCT every day; 1 RCT twice a day; 1 RCT 3 times
a week)
 Trial size, length and quality.
The first RCT442 not in the systematic review focused on the outcomes of symptoms, function and AEs
in N=60 patients with knee osteoarthritis. The RCT was a single blind, parallel group study and
compared low power laser treatment with placebo laser treatment (given once a day, 5 times a
week) in a 10 day treatment phase with 6 months follow-up. The second RCT508 not in the systematic
review focused on the outcomes of symptoms, function and AEs in N=55 patients with Knee
osteoarthritis. The RCT was a triple blind, parallel group study and compared laser acupuncture (laser
at acupuncture sites) + exercise with placebo laser acupuncture + exercise (given once a day, 5 times
a week) in a 2 week treatment phase with 12 weeks follow-up.
TENS
One SR/MA337 and 3 RCTs68,69,339 were found that focused on TENS.
The MA337 included 7 RCTs (with N=294 participants) that focused on comparisons between TENS and
AL-TENS versus placebo in patients with knee osteoarthritis. Studies included in the analysis differed
with respect to:
 Type of TENS used (4 RCTs High frequency TENS; 1 RCT Strong burst TENS; 1 RCT High frequency
and strong burst TENS; 1 RCT AL-TENS)

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Osteoarthritis
 Treatment regimen (modes of stimulation, optimal stimulation levels, pulse frequencies,

electrode placements, lengths of stimulation time and how often TENS was applied)
 Trial size, blinding, length, follow-up and quality
 Trial design (4 RCTs were parallel-group studies; 3 RCTs were cross-over studies).
The 3 RCTs68,69,339 not in the systematic review were parallel studies that focused on the outcomes of
symptoms, function and QoL in patients with knee osteoarthritis. The 2 studies by Cheing et al68,69
refer to the same RCT with different outcomes published in each paper. This RCT did not mention
blinding or ITT analysis but was otherwise methodologically sound. AL-TENS was compared to
placebo AL-TENS or exercise (all given 5 days a week) in N=66 patients in a 4 week treatment phase
with 4 weeks follow-up. The second RCT339 was methodologically sound (randomised and double-
blind) and compared TENS (given 5 times a week) versus intra-articular Hylan GF-20 injection (given
once a week) in N=60 patients with knee osteoarthritis in a 3 week treatment phase with 6 months
follow-up.
PEMF
Two SRs/MAs206,290 were found on PEMF.
The first MA206 included 3 RCTs (with N=259 participants) that focused on comparisons between
PEMF versus placebo PEMF in patients with knee osteoarthritis. All RCTs were high quality, double-
blind parallel group studies. Studies included in the analysis differed with respect to:
 Type of electromagnetic field used and treatment regimen (2 RCTs pulsed electromagnetic fields,
PEMF, using non-contact devise delivering 3 signals ranging from 5-12Hz frequency at 10 G to 25
G of magnetic energy. These used 9 hours of stimulation over 1 month period; 1 RCT use pulsed
electric devise delivering 100 Hz low-amplitude signal via skin surface electrodes for 6-10 hrs/day
for 4 weeks)
 Trial size and length.
The second MA290 included 5 RCTs (with N=276 participants) that focused on comparisons between
PEMF versus placebo PEMF in patients with Knee osteoarthritis. All RCTs were high quality,
randomised, double-blind parallel group studies. Studies included in the analysis differed with
respect to:
 Type of electromagnetic field used and treatment regimen (2 RCTs low frequency PEMF ranging
from 3-50Hz requiring long durations of treatment range 3-10 hrs/week; 3 RCTs used ‘pulsed
short wave’ high frequency devices with shorter treatment durations)
8.3.3 Evidence statements: ultrasound
Table 72: Pain

Knee or hip osteoarthritis
384
Pain (VAS), change 1 SR/MA 1 RCT, Ultrasound vs 4-6 weeks NS
from baseline N=74 placebo (end of
therapy) and
at 3 months (2
months post-
treatment).
384
Decrease in pain (VAS) 1 SR/MA 1 RCT, Ultrasound vs 3 weeks WMD –5.10, 95% CI
change from baseline N=120 galvanic current –9.52 to –0.68,

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Osteoarthritis

p=0.02
Favours galvanic
current
384
Pain (number of knees 1 SR/MA 1 RCT, Ultrasound vs Single NS
with subjective N=100 diathermy assessment -
improvement), change immediate
from baseline; Pain
(number of knees with
objective
improvement), change
from baseline
384
Decrease in pain (VAS) 1 SR/MA 1 RCT, Ultrasound vs Single NS
change from baseline N=120 diathermy assessment -
immediate
Table 73: Patient Function

384
Knee ROM (flexion 1 SR/MA 1 RCT, Ultrasound vs 4-6 weeks NS
and extension, N=74 placebo (end of
degrees), change from therapy) and
baseline at 3 months (2
months post-
treatment).

384
Patient and clinician 1 SR/MA 1 RCT, Ultrasound vs 3 weeks NS
global assessment N=108 galvanic current
(number of patients
‘good’ or ‘excellent’),
change from baseline
384
Patient and clinician 1 SR/MA 1 RCT, Ultrasound vs Single NS
global assessment N=120 diathermy assessment -
(number of patients immediate
‘good’ or ‘excellent’),
8.3.4 Evidence statements: laser
Table 75: Pain

Knee
442
Pain intensity at rest 1 RCT (N=60) Laser vs Placebo 3 weeks and 6 NS

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Osteoarthritis

(VAS); Pain intensity laser months
on activation (VAS); follow-up
WOMAC Pain
508
Pain (VAS); Medical RCT (N=55) Laser acupuncture 2 Weeks (end NS
tenderness score + exercise vs of treatment)
placebo laser and 12 weeks
acupuncture + (10 weeks
exercise post-
treatment
Mixed (Knee or hand or thumb or unspecified sites)
47
Number of patients 1 MA 1 RCT, N=8 Laser vs Placebo Not Peto OR 0.06, 95%
with no pain relief laser mentioned CI0.00 to 0.88,
p=0.04
Favours laser
47
Patient pain - different 1 MA 3 RCTs, Laser vs Placebo Not Significant
scales N=145 laser mentioned heterogeneity
Table 76: Stiffness

Knee
442
WOMAC stiffness 1 RCT (N=60) Laser vs Placebo 3 weeks and 6 NS
laser months
follow-up

Knee
442
WOMAC function 1 RCT (N=60) Laser vs Placebo 3 weeks and 6 NS
laser months
follow-up
508
WOMAC total; 50-foot RCT (N=55) Laser acupuncture 2 Weeks (end NS
walk time + exercise vs of treatment)
exercise post-
treatment
Table 78: Global asssessment

Mixed (Knee or hand or thumb or unspecified sites)
47
Patient global 1 MA 2 RCTs, Laser vs Placebo Not NS
assessment – N=110 laser mentioned
improved
47
Number of patients 1 MA 4 RCTs, Laser vs Placebo Not NS
improved on pain or N=147 laser mentioned

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Osteoarthritis

global assessment

Knee
508
Quality of Life (NHP RCT (N=55) Laser acupuncture 2 Weeks (end NS
score) + exercise vs of treatment)
exercise post-
treatment
Table 80: Adverse events

Knee
442
Number of AEs 1 RCT (N=60) Laser vs Placebo 3 weeks and 6 Both groups same
laser months (N=0)
follow-up
8.3.5 Evidence statements: TENS
Table 81: Pain

TENS / AL-TENS
Knee
337
Pain relief (VAS) 1 MA 6 RCTs, TENS/AL-TENS vs Study length: WMD –0.79, 95% CI
N=264 Placebo Range single –1.27 to –0.30,
treatment to 9 p=0.002
weeks Favours TENS / AL-
treatment; TENS
Followup:
range
immediate to
1 year
TENS
337
Number of patients 1 MA 5 RCTs, TENS vs Placebo Study length: Peto OR 3.91, 95%
with pain N=214 Range single CI 2.13 to 7.17,
improvement treatment to 9 p=0.00001
weeks Favours TENS
treatment;
Followup:
range
immediate to
1 year
337
Pain relief (VAS) 1 MA 5 RCTs, TENS vs Placebo Study length: Significant
N=214 Range single heterogeneity
treatment to 9

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weeks
treatment;
Followup:
range
immediate to
1 year
339
WOMAC Pain 1 RCT (N=60) TENS vs intra- 3 weeks (end NS
articular Hylan GF- of treatment)
20 and 1 month
and 6 months
post-
treatment.
AL-TENS
337
Pain at rest (pain 1 MA ; 1 AL-TENS vs Ice end of NS
509
intensity score, PPI) RCT (N=100) Massage treatment (2
weeks)
337
Pain relief (VAS) 1 MA 1 RCT, N=50 AL-TENS vs 2 weeks (end WMD –0.80, 95% CI
Placebo of treatment) –1.39 to –0.21,
p=0.007
69
Pain, VAS (difference 1 RCT (N=66) AL-TENS vs Day 1, 2 Day 1: -35.9 (AL-
between pre-and post- Placebo (sham AL- weeks (mid- TENS) and –15.5
treatment scores) TENS) treatment) (sham)
and 4 weeks 2 weeks: -7.9 (AL-
(end of TENS) and +2.7
treatment) (sham)
4 weeks: -11.9 (AL-
TENS) and –6.2
(sham)
AL-TENS better
69
Pain, VAS (difference 1 RCT (N=66) AL-TENS vs 4 weeks post- -7.8 (AL-TENS) and
between pre-and post- Placebo (sham AL- treatment –19.3 (sham)
treatment scores TENS) Placebo better
69
Pain, VAS (difference 1 RCT (N=66) AL-TENS vs Day 1, 4 Day 1: -35.9 (AL-
between pre-and post- exercise weeks (end of TENS) and +21.6
treatment scores) treatment) (exercise)
and 4 weeks 4 weeks: -11.9 (AL-
post- TENS) and -7.6
treatment (exercise)
4 weeks
posttreatment: -7.8
(AL-TENS) and
+42.0 (exercise)
AL-TENS better
69
Pain, VAS (difference 1 RCT (N=66) AL-TENS vs 2 weeks (mid- 2 weeks: -7.9 (AL-
between pre-and post- exercise treatment) TENS) and -9.1
treatment scores) (exercise)
Exercise better

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Table 82: Stiffness

Knee
TENS / AL-TENS
337
Knee stiffness 1 MA 2 RCTs, N=90 TENS/AL-TENS vs Immediate WMD –6.02, 95% CI
Placebo and 2 weeks –9.07 to –2.96,
(end of p=0.0001
treatment) Favours TENS / AL-
TENS
TENS
339
WOMAC Stiffness 1 RCT (N=60) TENS vs intra- 3 weeks (end NS
articular Hylan GF- of treatment
20
339
WOMAC Stiffness 1 RCT (N=60) TENS vs intra- 1 month post- 1 month post-
articular Hylan GF- treatment treatment
20 (p<0.007) and (p<0.007) and 6
6 months months post-
post- treatment (p<0.05).
treatment Favours intra-
(p<0.05). articular Hylan
AL-TENS
337
Knee stiffness 1 MA 1 RCT, N=50 AL-TENS vs 2 weeks (end WMD –7.90, 95% CI
Placebo of treatment) –11.18 to –4.62,
p<0.00001
Favours AL-TENS

TENS / AL-TENS
Knee
337
Pain relief (VAS) 1 MA 6 RCTs, TENS/AL-TENS vs Study length: WMD –0.79, 95%
N=264 Placebo Range single CI –1.27 to –0.30,
weeks Favours TENS / AL-
treatment; TENS
Followup:
range
immediate to
1 year
TENS
337
Number of patients 1 MA 5 RCTs, TENS vs Placebo Study length: Peto OR 3.91, 95%
with pain improvement N=214 Range single CI 2.13 to 7.17,
weeks Favours TENS
treatment;
Followup:
range
immediate to
1 year

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Osteoarthritis

337
Pain relief (VAS) 1 MA 5 RCTs, TENS vs Placebo Study length: Significant
N=214 Range single heterogeneity
treatment to 9
weeks
treatment;
Followup:
range
immediate to
1 year
339
Lequesne function 1 RCT (N=60) TENS vs intra- 3 weeks (end p<0.05
articular Hylan GF- of treatment Favours TENS
20
339
WOMAC function 1 RCT (N=60) TENS vs intra- 3 weeks (end NS
20 and 1 month
post-
treatment
339
Lequesne function 1 RCT (N=60) TENS vs intra- 1 and 6 NS
articular Hylan GF- months post-
20 treatment
339
Lequesne total 1 RCT (N=60) TENS vs intra- 3 weeks (end NS
20 and 1 month
and 6 months
post-
treatment
339
WOMAC function 1 RCT (N=60) TENS vs intra- 6 months p<0.05
articular Hylan GF- post- intra-articular
20 treatment Hylan G-F20 better
AL-TENS
337
50-foot walk time; 1 MA ; 1 AL-TENS vs Ice end of NS
509
Quadriceps muscle RCT (N=100) Massage treatment (2
strength (kg); Flexion weeks)
(degrees).
337
50-foot walking time 1 MA 1 RCT, N=50 AL-TENS vs 2 weeks (end WMD –22.60, 95%
(minutes) Placebo of treatment) CI –43.01 to –2.19,
p=0.03
Favours AL-TENS
337
Quadriceps muscle 1 MA 1 RCT, N=50 AL-TENS vs 2 weeks (end WMD –5.20, 95%
strength (kg) Placebo of treatment) CI –7.85 to –2.55,
p=0.0001
Favours AL-TENS
337
Knee flexion (degrees), 1 MA 1 RCT, N=50 AL-TENS vs 2 weeks (end WMD –11.30, 95%
Placebo of treatment) CI –17.59 to –5.01,
p=0.0004
Favours AL-TENS
69
Stride length (m) at 4 1 RCT (N=66) AL-TENS vs 4 weeks (end 4 weeks: 1.06 (AL-
weeks Placebo (sham AL- of treatment) TENS) and 1.02
TENS) and 4 weeks (sham)
post- 4 weeks post-

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Osteoarthritis

treatment treatment: 1.07
(AL-TENS) and 1.04
(sham)
AL-TENS better
69
Cadence (steps/min) 1 RCT (N=66) AL-TENS vs 4 weeks (end 4 weeks: 109 (AL-
Placebo (sham AL- of treatment) TENS) and 108
post- 4 weeks post-
treatment treatment: 110 (AL-
TENS) and 107
(sham)
AL-TENS better
69
Velocity (m/s) at 4 1 RCT (N=66) AL-TENS vs 4 weeks (end 4 weeks: 0.97 (AL-
weeks Placebo (sham AL- of treatment) TENS) and 0.92
post- 4 weeks post-
(AL-TENS) and 0.93
(sham)
AL-TENS better
69
ROM during walking 1 RCT (N=66) AL-TENS vs 4 weeks (end 4 weeks: 51.8 (AL-
(degrees) Placebo (sham AL- of treatment) TENS) and 51.5
post- 4 weeks post-
(AL-TENS) and 51.2
(sham)
AL-TENS better
69
ROM at rest (degrees) 1 RCT (N=66) AL-TENS vs 4 weeks post- 106 (AL-TENS) and
at 4 weeks post- Placebo (sham AL- treatment 103 (sham)
treatment (106 and 103 TENS) AL-TENS better
respectively).
69
ROM at rest (degrees) 1 RCT (N=66) AL-TENS vs 4 weeks, end Both groups the
Placebo (sham AL- of treatment same
TENS)
69
Isometric peak torque 1 RCT (N=66) AL-TENS vs day 1, 2 weeks NS
of knee extensors and Placebo (sham AL- (mid
flexors at specified TENS) treatment), 4
knee positions weeks (end of
treatment)
and at 4
weeks post-
treatment
69
Stride length (m) at 1 RCT (N=66) AL-TENS vs Day 1 and 2 Day 1: 0.95 (AL-
Placebo (sham AL- weeks, mid- TENS) and 0.99
TENS) treatment (sham)
2 weeks: 1.01 (AL-
TENS) and 1.02
(sham)
Sham better

158
Osteoarthritis

69
Cadence (steps/min) at 1 RCT (N=66) AL-TENS vs Day 1 and 2 Day 1: 100 (AL-
Velocity (m/s) Placebo (sham AL- weeks, mid- TENS) and 103
2 weeks: 105 (AL-
TENS) and 108
(sham)
Sham better
69
ROM during walking 1 RCT (N=66) AL-TENS vs Day 1 and 2 Day 1: 50.3 (AL-
(degrees) Placebo (sham AL- weeks, mid- TENS) and 51.3
2 weeks: 51.7 (AL-
TENS) and 52.3
(sham)
Sham better
69
ROM at rest (degrees) 1 RCT (N=66) AL-TENS vs Day 1 and 2 Day 1: 104 (AL-
Placebo (sham AL- weeks, mid- TENS) and 107
2 weeks: 102 (AL-
TENS) and 104
(sham)
Sham better
69
Stride length (m) 1 RCT (N=66) AL-TENS vs 4 weeks, end 4 weeks: 1.06 (AL-
exercise of treatment TENS) and 1.03
and 4 weeks (exercise)
post- 4 weeks post-
(AL-TENS) and 1.03
(exercise)
AL-TENS better
69
Cadence (steps/min) 1 RCT (N=66) AL-TENS vs 4 weeks, end 4 weeks: 109 (AL-
exercise of treatment TENS) and 104
post- 4 weeks post-
TENS) and 107
(exercise)
AL-TENS better
69
Velocity (m/s) 1 RCT (N=66) AL-TENS vs 4 weeks, end 4 weeks: 0.97 (AL-
exercise of treatment TENS) and 0.89
post- 4 weeks post-
(AL-TENS) and 0.92
(exercise)
AL-TENS better
69
ROM during walking 1 RCT (N=66) AL-TENS vs Day 1, 2 Day 1: 50.3 (AL-
(degrees) exercise weeks (mid TENS) and 48.7
treatment), 4 (exercise)
weeks (end of 2 weeks: 51.7 (AL-
treatment) TENS) and 48.6
post-

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Osteoarthritis

treatment 4 weeks: 51.8 (AL-
TENS) and 48.7
(exercise)
4 weeks post-
treatment: 53.1
(AL-TENS) and 48.3
(exercise)
AL-TENS better
69
ROM at rest (degrees) 1 RCT (N=66) AL-TENS vs 4 weeks, end 4 weeks: 107 (AL-
exercise of treatment TENS) and 106
post- 4 weeks post-
TENS) and 104
(exercise)
AL-TENS better
69
Peak torque of knee 1 RCT (N=66) AL-TENS vs day 1, 2 weeks NS
extensors and flexors at exercise (mid
specified knee treatment), 4
positions weeks (end of
treatment)
and at 4
weeks post-
treatment.
69
Stride length (m) 1 RCT (N=66) AL-TENS vs Day 1 and 2 Day 1: 0.95 (AL-
exercise weeks (mid- TENS) and 1.00
treatment) (exercise)
2 weeks: 1.01 (AL-
TENS) and 1.02
(exercise)
Exercise better
69
Cadence (steps/min) 1 RCT (N=66) AL-TENS vs Day 1 and 2 Day 1: 100 (AL-
exercise weeks (mid- TENS) and 104
2 weeks: 105 (AL-
TENS) and 106
(exercise)
Exercise better
69
Velocity (m/s) 1 RCT (N=66) AL-TENS vs Day 1 and 2 Day 1: 0.81 (AL-
exercise weeks (mid- TENS) and 0.87
2 weeks: 0.89 (AL-
TENS) and 0.90
(exercise)
Exercise better
69
ROM at rest (degrees) 1 RCT (N=66) AL-TENS vs Day 1 and 2 Day 1: 104 (AL-
at Day 1 (104 and 105 exercise weeks (mid- TENS) and 105
respectively) and 2 treatment) (exercise)
weeks, mid-treatment 2 weeks: 102 (AL-
(102 and 105 TENS) and 105
respectively) (exercise)
Exercise better

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Osteoarthritis

Knee
TENS
339
SF-36 all dimensions 1 RCT (N=60) TENS vs intra- 3 weeks (end NS
articular Hylan GF- of treatment,
20 1 month and 6
months post-
treatment

Knee
TENS
339
Number of withdrawals 1 RCT (N=60) TENS vs intra- 6 months 10% (TENS) and
articular Hylan G- post- 17% (intra-articular
F20 treatment Hylan G-F20).
TENS better
339
Number of withdrawals 1 RCT (N=60) TENS vs intra- 6 months N=0 (TENS) and
articular Hylan G- post- N=2 (intra-articular
F20 treatment Hylan G-F20).
AL-TENS better
8.3.6 Evidence statements: PEMF
Table 86: Pain

Knee
PEMF
206
Joint pain on motion 1 MA PEMF vs placebo 4 weeks and 1 SMD: -0.59, 95% CI
PEMF month –0.98 to –2.0
Favours PEMF
206
Improvements in knee MA PEMF vs placebo 4 weeks and 1 SMD –0.91, 95% CI
tenderness PEMF month –1.20 to –0.62)
Favours PEMF
206
Pain (ADL) 1 MA PEMF vs placebo 4 weeks and 1 SMD –0.41, 95% CI
Favours PEMF
290
Pain (WOMAC and VAS) 1 MA 5 RCTs, PEMF vs placebo 2 – 6 weeks NS
N=276 PEMF

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Osteoarthritis
Table 87: Stiffness

Knee
PEMF
206
>15 minutes 1 MA 1 RCT, N=71 PEMF vs placebo 4 weeks and 1 NS
improvement in PEMF month
morning stiffness and
0-14 minutes
improvement in
morning stiffness.
Table 88: Function

Knee
PEMF
206
Number of patients 1 MA 1 RCT, N=71 PEMF vs placebo 4 weeks and 1 OR 0.27, 95% CI
with 5 degrees PEMF month 0.09 to 0.82,
improvement in flexion p=0.02
Favours PEMF
206
Difficulty (ADL) MA PEMF vs placebo 4 weeks and 1 SMD –0.71, 95% CI
Favours PEMF
206
Number of patients 1 MA 1 RCT, N=71 PEMF vs placebo 4 weeks and 1 Favours PEMF
with 0-4 degrees PEMF month
improvement in flexion
290
Function (WOMAC and 1 MA 5 RCTs, PEMF vs placebo 2 – 6 weeks NS
AIMS) N=228 PEMF

Knee
PEMF
206
Physician’s global 1 MA 1 RCT, N=71 PEMF vs placebo 4 weeks and 1 SMD –0.71, 95% CI
assessment PEMF month –1.11 to –0.31
Favours PEMF
290
Patient’s global 1 MA 2 RCTs, PEMF vs placebo 2 – 6 weeks NS
assessment N=108 PEMF

QoL assessment Assessment Outcome / Effect
Knee
PEMF
206 362
improvement in 1 MA 1 RCT , PEMF vs placebo 6 weeks (end SMD –0.71, 95% CI
EuroQoL perception of N=75 PEMF of treatment) –1.11 to –0.31
health status Favours PEMF

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Osteoarthritis
QoL assessment Assessment Outcome / Effect

290 57
AIMS score 1 MA 1 RCT , PEMF vs placebo 2 weeks (end +0.3 (low and high
N=27 PEMF of treatment) dose PEMF) and -
0.2 (placebo PEMF)
PEMF better
290 244
Pattern of change in 1 MA 1 RCT , PEMF vs placebo Over 12 weeks NS
GHQ score over time N=90 PEMF (8 weeks post-
treatment)

AEs assessment Assessment Outcome / Effect
Knee
PEMF
290 362
Number of patients 1 MA 1 RCT , PEMF vs placebo 6 weeks (end 2.7% (PEMF) and
with AEs N=75 PEMF of treatment) 5.3% placebo PEMF
Favours PEMF
206
Adverse skin reactions 1 MA 1 RCT, PEMF vs placebo 4 weeks and 1 NS
N=71 PEMF month
290 446
Number of patients 1 MA 1 RCT , PEMF vs placebo 2 weeks (mid- 13.3% (PEMF) and
with mild AEs. N=90 PEMF teatment) 6.7% (placebo
PEMF)
Placebo better

Knee
PEMF
206
Total withdrawals 1 MA 3 RCTs, PEMF vs placebo 4 weeks and 1 NS
N=184 PEMF month

Studies had varying methodological quality and detail on treatment dosages. There was evidence
that ultrasound provided no benefit beyond placebo ultrasound or other electrotherapy agents in
the treatment of knee and hip osteoarthritis384. There was no evidence for the benefit of laser for
pain relief at mixed sites of osteoarthritis from a systematic review48, but a recent study508 points to
the benefit of laser at acupuncture points in reducing knee swelling. Evidence for the benefits of
pulsed electromagnetic energy for osteoarthritis was limited in knee osteoarthritis290. In the hip and
hand no studies were identified. Ultrasound, laser and pulsed electromagnetic energy are well suited
for small joints such as hand and foot, but there is insufficient evidence to support their efficacy or
clinical effectiveness in osteoarthritis. Further research would be helpful in these areas because it is
not clear if efficacy or safety can be extrapolated from knee studies, and a research recommendation
is included on this area. Given that there is no evidence on harm caused by laser, ultrasound or
pulsed electromagnetic fields the GDG have not made a negative recommendation on these.
There is evidence that TENS is clinically beneficial for pain relief and reduction of stiffness in knee
osteoarthritis especially in the short term however this was not shown in a community setting. There
is no evidence that efficacy tails off over time, or that periodic use for exacerbations is helpful.

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Osteoarthritis
Proper training for people with osteoarthritis in the placing of pads and selection of stimulation
intensity could make a difference to the benefit they obtain. Good practice guidance recommends an
assessment visit with the health professional with proper training in the selection of stimulation
intensity (e.g. low intensity, once a day, 40 minutes duration, 80Hz, 140 microseconds pulse) with
reinforcement with an instruction booklet. People with osteoarthritis should be encouraged to
experiment with intensities and duration of application if the desired relief of symptoms is not
initially achieved. This enables patients control of their symptoms as part of a self-management
approach. A further follow up visit is essential allowing the health professional to check patients’
usage of TENS and problem solve. No adverse events or toxicity have been reported with TENS.
Contraindications include active implants (pacemakers, devices with batteries giving active
medication); the contraindication of the first three months of pregnancy is currently under review
(CSP guidelines). Although adverse events from TENS such as local skin reactions and allergies to the
adhesive pads are known, they are rare.
As with all therapies adjunctive to the core treatments (see algorithm), it is important that the
individual with osteoarthritis is able to assess the benefit they obtain from electrotherapy and take
part in treatment decisions.
15.Healthcare professionals should consider the use of transcutaneous electrical nerve stimulation
(TENS)f as an adjunct to core treatments for pain relief. [2008]
8.4 Nutraceuticals
8.4.1 Introduction
Nutraceuticals is a term used to cover foods or food supplements thought to have health benefits.
The most widely used is glucosamine (sulfate and hydrochloride) which is widely sold in various
combinations, compounds, strengths and purities over the counter in the UK. Medical quality
glucosamine sulfate and hydrochloride are licensed in the European Union and can be prescribed.
These compounds are not licensed by the Food and Drug Administration in the USA, so are marketed
there (and on the internet) as health food supplements.
Update 2014
Glucosamine is an amino sugar and an important precursor in the biochemical synthesis of
glycosylated proteins, including glycosaminoglycans. The sulfate moiety of glucosamine sulfate is
associated with the amino group. Chondroitin sulfate is a sulfated glycosaminoglycan (GAG) dimer,
which can be polymerised to the chain of alternating sugars (N-acetylgalactosamine and glucuronic
acid) found attached to proteins as part of a proteoglycan. It is hypothesised that substrate
availability (of glucosamine, chondroitin or sulfate itself) may be the limiting factor in the synthesis of
the GAG component of cartilage, which provides the rationale for oral supplementation of these
compounds in osteoarthritis. The mode of action and both in vitro and in vivo effects of these
compounds remain highly controversial, although their safety is rarely disputed. The GDG wished to
review the evidence on the use of nutraceuticals in the management of OA.
f
TENS machines are generally loaned to the person by the NHS for a short period, and if effective the person is advised
where they can purchase their own.

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Osteoarthritis
8.4.2 What is the clinical and cost effectiveness of glucosamine and chondroitin alone or in
compound form versus placebo or other treatments in the management of osteoarthritis?

Population Adults with a clinical diagnosis of OA
Intervention/s
Preparations of (any route of administration)
 Glucosamine (sulfate or hydrochloride)
 chondroitin
 Glucosamine + chondroitin
Comparison/s  Placebo
 Paracetamol
 Oral and topical NSAIDs
 NSAIDs +PPI
 Selective COX-2 inhibitors including 30 mg etoricoxib
 Selective COX-2 inhibitors including 30 mg etoricoxib + PPI
 Paracetamol + opioids
Outcomes  Global joint pain (VAS, NRS or WOMAC pain subscale, WOMAC for knee and hip
Update 2014
only, AUSCAN subscale for hand)
 Function (WOMAC function subscale for hip or knee or equivalent such as AUSCAN
function subscale or Cochin or FIHOA for hand and change from baseline)
 Stiffness (WOMAC stiffness score change from baseline)
 Structure modification
 Adverse events (GI, renal and cardiovascular)
Study design
Systematic reviews and meta-analyses
RCTs
Conference abstracts for unpublished trials if no RCTs retrieved

We searched for systematic reviews and randomised trials assessing the effectiveness of
nutraceuticals in the management of osteoarthritis. The GDG agreed that the evidence should be
stratified according to licensing indication of the nutraceuticals in the UK to inform decisions related
to recommendations for the NHS.

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Osteoarthritis
The GDG noted that any degree of structure modification should be taken as clinically important,
thus the MID chosen for structural modification outcomes was the line of no effect or zero
Glucosamine
One Cochrane review which included 25 RCTs was identified for this question 458. In addition, three
studies were identified that were published after the Cochrane review 154,165,401. Evidence from these
are summarised in the clinical GRADE evidence profile below. See also the study selection flow chart
in Appendix D, forest plots in Appendix I, study evidence tables in Appendix G and exclusion list in
Appendix J.
Of the 25 RCTs included in the Cochrane review, eight studies had a population with primary
osteoarthritis, whilst the remaining studies did not clarify whether the population had primary or
secondary OA.
Twenty studies included in the Cochrane review evaluated the use of nutraceuticals in knee OA, and
one looked exclusively at people with hip OA. The three papers published after the Cochrane review
all had populations with knee OA. Two studies assessed OA at multiple sites and two studies did not
specify the site of OA. These studies were not included in the review because the view is that these
studies do not add to the GDG’s understanding of how an agent works on the single site and they do
not assist in understanding how therapies might help multiple joint patients.
The route of administration of glucosamine differed between studies included in the Cochrane
review. Twenty-one studies used an oral route, two used an intra-articular (IA) route, three used an
intramuscular (IM) route, one used an intravenous (IV) route, and two studies used multiple routes
of administration. The three papers identified that were published after the Cochrane review all used
Update 2014
oral route of administration. All studies allowed the use of paracetamol with/without NSAIDS as
rescue medication.
The dosage of glucosamine differed between studies included in the Cochrane review. The dose of
glusosamine was 1500mg per day in studies administering glucosamine orally, although the division
of doses differed between studies. In the RCTs using parenteral routes, the dosage was 400mg once
daily in two studies, and twice per week in another study. In the three papers identified published
after the Cochrane, one study used 1500mg per day401, one used approximately 500mg per day154
and in the other study it was assumed that 1500mg per day was administered, although this is not
clear165.
The studies included in the Cochrane had varying length of follow up, ranging from 3 weeks to 3
years. The mean trial duration was 25.5 weeks. Of the three papers identified that were published
after the Cochrane, one had 12 weeks follow up154, one had 24 weeks follow up165 and one had 2
years follow up401.
Data in the meta-analysis has been stratified by joint type and by licensing indication. The GDG
indicated that the licensed glucosamine sulfate preparation from the Rottapharm group is available
in the UK as Glusartel. All relevant studies assessing licensed glucosamine sulfate were reviewed
and stratified accordingly either based on the information provided in the study or as indicated by
the Cochrane Review. The GDG are aware of licensed preparations of glucosamine hydrochloride, but
none of the retrieved studies has referred to a licensed preparation. No separate analysis of studies
with unlicensed preparations of glucosamine sulfate was undertaken as it was recognised that such
studies may have potentially involved the use of preparations licensed outside of the UK.
One study that was included in the Cochrane review was only available as a published abstract 392.
The study quality had been assessed by the Cochrane group, but the GDG were interested in the
effect that this data had on the overall results, therefore a sensitivity analysis was undertaken
excluding the Rovati study from glucosamine hydrochloride and sulfate (licensed and unlicensed
formulations) versus placebo and glucosamine sulfate (licensed formulation) versus placebo
analyses. No sensitivity analysis was undertaken on glucosamine vs NSAID analysis because the
Rovati (1997) study was the only study included in this review.

166
Osteoarthritis
Sensitivity analyses were also conducted where significant heterogeneity was present. This included
looking at the different time points for reporting outcomes and if heterogeneity was still present, to
conduct sensitivity analyses on studies with very high risk of bias.
Data from Sawitze (2008) and Sawitze (2010) have not been included in the meta-analysis (but are
included in the evidence review) due to their data reporting; as only mean values without standard
deviations, standard errors or confidence intervals were provided. Furthermore, Sawitze (2008) and
(2010) were not adequately randomised studies.
One post-hoc analysis 52 of two RCTs conducted in people with knee OA 344 375 was included in the
review; the study had an 8 year observation period. The GDG thought that this study provided
important information on long-term joint replacement outcomes that were not captured in the RCT
evidence review. Only information on the number of people who had knee replacements could be
extracted from this study. The study also reported that the NNT was 12 (indicating that 12 people
needed to take glucosamine sulfate to avoid 1 knee replacement). Time to joint replacement was
also reported using a Log-rank test; a p value of 0.026 was reported indicating that there is a
decreased and delayed cumulative incidence of total knee replacement for people who had
previously taken glucosamine sulfate.
One RCT conference abstract343 in hand OA was also identified and its data presented in a seprate
GRADE table.
Chondroitin
One meta-analysis which included 22 trials was included in this review376. One study included in the
meta-analysis was a non-randomised study and the findings have not been included in the analysis of
this review424.In addition, seven studies were identified that were published after the meta-
Update 2014
analysis157,229,316,370,402,492,511. One study was identified as a non-randomised post hoc analysis of one of
the studies included in the meta-analysis and the findings, although presented in evidence tables, are
not included in the analysis402.
Evidence from these are summarised in the clinical GRADE evidence profile below (See tables 5-9).
See also the study selection flow chart in Appendix D, forest plots in Appendix I, study evidence
tables in Appendix G and exclusion list in Appendix J.
The meta-analysis376 was assessed using the NICE checklist for quality assessment of systematic
reviews and was found to meet the inclusion criteria for this review. An adequate risk of bias
assessment was undertaken in the meta-analysis and this has been included in this review for
reporting risk of bias of the studies included in the meta- analysis. The studies identified after the
meta-analysis were assessed for risk of bias using the NICE checklist for quality assessment of
randomised trials.
Of the 22 studies included in the meta-analysis, seventeen trials were published as full text articles
and five were published as conference abstracts at time of publication of the meta- analysis. Since
then, three studies have been published as full text articles 229,285,465 and relevant data has been
extracted from these publications and has been included in this review.
Seventeen studies included in the meta- analysis evaluated the use of chondroitin in osteoarthritis of
the knee, two looked at knee or hip and one study looked at hip OA. In the trials identified after the
meta-analysis, four trials were in knee OA and one was in OA of the hand.
All studies included in the clinical evidence review included unlicensed preparations of chondroitin.
The route of administration of chondrotin in all studies included in this review was oral except for
two studies included in the meta-analysis, where chondroitin was administered intra-
muscularly238,393. The daily dose of chondroitin taken differed between studies. In the meta-analysis,
among studies reporting oral dosing of chondroitin, eight studies had doses of 800mg, six studies had
doses of 100mg, six studies had doses of 1200mg, one study had a dose of 1000mg and one study
had a dose of 2000mg. Chondroitin was administered on consecutive days in nineteen trials and

167
Osteoarthritis
intermittently in three trials83,275,424. Of the two studies using intra-muscular preparations, one used
150 biological units238 and the dosage was not reported in the other study393. In the studies identified
after the meta-analysis, four reported doses of 800 mg daily and one reported a dose of 1200 mg
daily. All studies allowed the use of paracetamol with/without NSAIDS as rescue medication.
The studies included in the meta-analysis had varying lengths of follow up, ranging from 13 to 132
weeks with a median duration of 31 weeks. The length of follow up in the trials identified after the
meta-analysis ranged from 3 months to 2 years.
Sensitivity analyses were also conducted where significant heterogeneity was present. This included
looking at the different time points for reporting outcomes and if heterogeneity was still present, to
conduct sensitivity analyses on studies with very high risk of bias.
Glucosamine + Chondroitin
Three studies that compared glucosamine hydrochloride+ chondroitin vs placebo were included in
CG5981,98,369. Four studies published after CG59 that compared glucosamine hydrochloride+
chondroitin sulfate to placebo were identified 78,305,401,402. Three of these studies were three- armed
trials that also compared glucosamine hydrochloride+ chondroitin sulfate to NSAIDs 78,305,401,402. The
NSAID used in all of these studies was Celecoxib. Two of the studies comparing glucosamine
hydrochloride+ chondroitin sulfate to NSAIDs could not be meta-analysed due to reasons reported
above 401,402. All studies allowed the use of paracetamol with/without NSAIDS as rescue medication.

Study Intervention/comparison Population Comments
511
Zegels 2013 Chondroitin sulfate vs placebo People with Knee OA
Update 2014
370
Railhac 2012 Chondroitin sulfate vs placebo People with Knee OA
343
Patru 2012 Glucosamine sulfate vs People with Hand OA Conference
paracetamol abstract only.
Frestedt 2008 Glucosamine sulfate vs placebo People with Knee OA
Giordano 2009 Glucosamine sulfate vs placebo People with Knee OA
Sawitze 2008 and 2010 Glucosamine hydrochloride vs People with Knee OA Data not
placebo included in
Chondroitin sulfate vs placebo meta-analysis.
Study not
properly blinded
Towheed 2009 23 RCTs comparing glucosamine People with Cochrane review
sulfate and 2 RCTs comparing osteoarthritis. 20
glucosamine hydrochloride to RCTs on knee OA, 1
placebo RCT on Hip OA, 2 on
4 RCTs comparing glucosamine mixed OA sites and 2
sulfate to and one RCT comparing RCT did not specify
glucosamine hydrochloride to
NSAIDs
Gabay 2011 Chondroitin sulfate vs placebo People with hand OA
Kahan2009 Chondroitin sulfate vs placebo People with Knee OA
Moller2010 Chondroitin sulfate vs placebo People with Knee OA
Wildi2011 Chondroitin sulfate vs placebo People with Knee OA
Sawitzke2010 Chondroitin sulfate vs placebo People with Knee OA Non randomised
post hoc analysis
of Clegg 2006;
data not
included in

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Osteoarthritis
Study Intervention/comparison Population Comments

meta-analysis.
Reichenbach2007 22 RCTs, All comparing chondroitin People with OA; 17 Meta-analysis;
sulfate to placebo and one RCTs- Knee OA, 1 included in CG59
comparing chondroitin sulfate to RCT- Hip OA, 2 RCTs-
NSAIDs Knee/Hip OA
Messier 2007 Glucosamine hydrochloride + People with Knee OA
chondroitin sulfate vs placebo
Clegg 2006 Glucosamine hydrochloride + People with Knee OA
chondroitin sulfate vs Glucosamine
hydrochloride vs Chondroitin
sulfate vs placebo vs NSAIDs
Das & Hammad 2000 Glucosamine hydrochloride + People with Knee OA Included in
Chondroitin sulfate vs Placebo GC59. The
intervention
group tablet also
included
Manganese
ascorbate.
Cohen 2003 Glucosamine hydrochloride + People with Knee OA Included in GC59
Chondroitin sulfate vs Placebo
Rai 2004 Glucosamine hydrochloride + People with Knee OA Included in
Chondroitin sulfate vs Placebo GC59. Could not
be included in
Update 2014
the meta-
analysis
Additional systematic reviews were identified relating to the clinical and cost effectiveness of
nutraceuticals. Firstly, a Health Technology Assessment, The clinical effectiveness of glucosamine and
chondroitin supplements in slowing or arresting progression of osteoarthritis of the knee: a
systematic review and economic evaluation (2009) 39. This HTA comprised a review of systematic
reviews and an economic evaluation, in which the Towheed (2005), Reichenbach (2007) and the
original guideline (2008) were included. Therefore, the HTA was not used as the basis for the
updated meta-analyses conducted for the nutraceuticals review, but was used as a quality assurance
tool to cross-refer for any missed studies.
Secondly, a systematic review conducted as part of an assessment of whether the OARSI

recommendations should be modified in light of recent evidence was also identified 513.The
systematic review identified 64 systematic reviews, 266 RCTs and 21 economic evaluation’s that met
the inclusion criteria. Again, the OARSI meta-analyses were not used as the basis for the updated
meta-analyses conducted for the nutraceuticals review, as only effect sizes were published and raw
data of the individual studies was not available from the published study
The GDG were also aware of a network meta-analysis 481 which compared glucosamine, chondroitin,
and their combination with placebo and showed that there was no reduction in joint pain or an
impact on narrowing of joint space. The effect sizes of this NMA were not used in our analyses as the
study was published in 2010 (and new studies have been published since then) and stratification of
results was different from the strata set out in the protocol for this evidence review

169
Osteoarthritis
Table 95: Glucosamine hydrochloride and sulfate versus placebo (Knee and hip)
Glucosamine versus Quality Importance

No of Risk of Other placebo- subgroup by joint Relative
Design Inconsistency Indirectness Imprecision Control Absolute
studies bias considerations type and length of follow (95% CI)
up
Pain (pooled measures) (Knee OA) (Better indicated by lower values): Giordano 2009; Houpt 1999; Hughes 2002; McAlindon 2004; Pujalte 1980; Rindone 2000; Usha 2004; Vajaradul
1981; Cibere 2004; Clegg 2006; Pavelka 2002; Herrero-Beaumont 2007; Rovati 1997, Reginster 2001
14 randomised seriousa very seriousb no serious no serious None 1112 1106 - SMD 0.28 lower CRITICAL
trials indirectness imprecision (0.49 to 0.08 VERY LOW
lower)
Pain (pooled measures) (Knee OA) - 3 months or less (Better indicated by lower values): Giordano 2009; Houpt 1999; Hughes 2002; McAlindon 2004; Pujalte 1980; Rindone 2000; Usha
2004; Vajaradul 1981
8 randomised very seriousb no serious seriousc None 332 339 - SMD 0.29 lower CRITICAL
a
trials serious indirectness (0.57 lower to 0 VERY LOW
higher)
Pain (pooled measures) (Knee OA) - more than 3 months treatment (Better indicated by lower values): Cibere 2004; Clegg 2006; Pavelka 2002; Herrero-Beaumont 2007; Rovati 1997,
Update 2014
Reginster 2001
6 randomised seriousa very seriousb no serious seriousc None 780 767 - SMD 0.28 lower CRITICAL
trials indirectness (0.59 lower to VERY LOW
0.03 higher)
WOMAC Pain Subscale (Knee OA) (Better indicated by lower values): Frestedt 2008; Giordano 2009; Houpt 1999; Hughes 2002; McAlindon 2004; Cibere 2004; Clegg 2006; Pavelka 2002;
Herrero-Beaumont 2007; Reginster 2001
10 randomised seriousa no serious no serious no serious None 935 932 - SMD 0.05 lower CRITICAL
trials inconsistency indirectness imprecision (0.14 lower to MODERATE
0.04 higher)
WOMAC Pain Subscale (Knee OA) - up to and including 3 months treatment (Better indicated by lower values): Frestedt 2008; Giordano 2009; Houpt 1999; Hughes 2002; McAlindon
2004
5 randomised seriousa seriousb no serious no serious None 234 242 - SMD 0.03 higher CRITICAL
trials indirectness imprecision (0.15 lower to LOW
0.21 higher)
WOMAC Pain Subscale (Knee OA) - more than 3 months treatment (Better indicated by lower values): Cibere 2004; Clegg 2006; Pavelka 2002; Herrero-Beaumont 2007; Reginster 2001
0.02 higher)
WOMAC Function Subscale (Knee OA) (Better indicated by lower values) Frestedt 2008; Giordano 2009; Houpt 1999; Hughes 2002; McAlindon 2004; Cibere 2004; Clegg 2006; Pavelka
2002; Herrero-Beaumont 2007; Reginster 2001
0.01 higher)
WOMAC Function Subscale (Knee OA) - up to and including 3 months treatment (Better indicated by lower values) ) Giordano 2009; Frestedt 2008; Houpt 1999; Hughes 2002;
McAlindon 2004
National Clinical Guideline Centre, 2014 170

Osteoarthritis
0.16 higher)
WOMAC Function Subscale (Knee OA) - more than 3 months treatment (Better indicated by lower values); Cibere 200476,7786,8786,87; Clegg 2006; Pavelka 2002; Herrero-Beaumont 2007;
Reginster 2001
trials inconsistency indirectness imprecision (0.2 lower to 0.01 MODERATE
higher)
WOMAC Stiffness Subscale (Knee OA) (Better indicated by lower values) Frestedt 2008; Giordano 2009; Houpt 1999; Hughes 2002; Cibere 2004; Clegg 2006; Pavelka 2002
7 randomised very no serious no serious no serious None 622 618 - SMD 0.02 lower LOW CRITICAL
trials seriousa inconsistency indirectness imprecision (0.13 lower to
0.09 higher)
WOMAC Stiffness Subscale (Knee OA) - 3 months or less (Better indicated by lower values): Giordano 2009; Frestedt 2008; Houpt 1999; Hughes 2002 - unlicensed preparation only
4 randomised very seriousb no serious no serious None 133 138 - SMD 0.06 higher CRITICAL
trials seriousa indirectness imprecision (0.18 lower to 0.3 VERY LOW
higher)
WOMAC Stiffness Subscale (Knee OA) - more than 3 months (Better indicated by lower values): Cibere 200476,7786,8786,87; Clegg 2006; Pavelka 2002
3 randomised very no serious no serious no serious None 489 480 - SMD 0.04 lower CRITICAL
trials seriousa inconsistency indirectness imprecision (0.16 lower to LOW
Update 2014
0.09 higher)
VAS pain on movement (3 months or less) (Knee OA) (Better indicated by lower values) Giordano 2009unlicensed preparation only
1 randomised seriousa no serious no serious seriousc None 30 30 - SMD -0.54 lower CRITICAL
trials inconsistency indirectness (1.05 to 0.02 LOW
lower)
VAS pain at rest (Knee OA) - 3 months or less (Better indicated by lower values) Giordano 2009 unlicensed preparation only
1 randomised seriousa no serious no serious seriousc None 30 30 - SMD 0.76 lower LOW CRITICAL
trials inconsistency indirectness (1.29 to 0.24
lower)
VAS pain at rest (Knee OA) - more than 3 months (Better indicated by lower values) Giordano 2009- unlicensed preparation only
1 randomised seriousa no serious no serious seriousc None 30 30 - SMD 0.04 lower LOW CRITICAL
trials inconsistency indirectness (0.55 lower to
0.46 higher)
Patient global assessment of disease status score (0-100mm scale)- unlicensed preparation only- More than 3 months (Better indicated by higher values) Clegg 2006
1 randomised very no serious no serious no serious None 317 313 - SMD 0.04 higher IMPORTANT
0.20 higher)
Patient global assessment - number responding they are better than at start of trial -)- unlicensed preparation only 3 months or less- Houpt 1999
1 randomised very no serious no serious seriousc None 28/58 24/60 RR 1.21 84 more per 1000 IMPORTANT
trials seriousa inconsistency indirectness (48.3%) (40%) (0.8 to (from 80 fewer to VERY LOW
1.82) 328 more)
Osteoarthritis Research Society International Responder Criteria (OARSI) (Knee OA) Hughes 2002; Clegg 2006; Herrero-Beaumont 2007
3 randomised seriousa very seriousb no serious seriousc None 246/462 213/456 RR 1.23 107 more per IMPORTANT
trials indirectness (53.2%) (46.7%) (0.83 to 1000 (from 79 VERY LOW
1.83) fewer to 388
more)

Osteoarthritis
Osteoarthritis Research Society International Responder Criteria (OARSI) (Knee OA) - 3 months or less- Hughes 2002- unlicensed preparation only
1 randomised no serious no serious no serious very seriousc None 12/39 13/39 RR 0.92 27 fewer per 1000 IMPORTANT
trials risk of bias inconsistency indirectness (30.8%) (33.3%) (0.48 to (from 173 fewer to LOW
1.76) 253 more)
Osteoarthritis Research Society International Responder Criteria (OARSI) (Knee OA) - more than 3 months- Clegg 2006; Herrero-Beaumont 2007
2 randomised seriousa very seriousb no serious seriousc None 234/423 200/417 RR 1.36 173 more per IMPORTANT
trials indirectness (55.3%) (48%) (0.78 to 1000 (from 106 VERY LOW
2.38) fewer to 662
more)
Toxicity (Number of Patients Reporting Adverse Events) (Knee OA) Frestedt 2008; Houpt 1999; Hughes 2002; McAlindon 2004; Noack 1994; Pujalte 1980; Reichelt 1994; Rindone 2000;
Vajaradul 1981; Herrero-Beaumont 2007; Pavelka 2002; Reginster 2001; Rovati 1997
13 randomised seriousa no serious no serious no serious None 365/894 366/896 RR 0.99 4 fewer per 1000 IMPORTANT
trials inconsistency indirectness imprecision (40.8%) (40.8%) (0.91 to (from 37 fewer to MODERATE
1.07) 29 more)
Toxicity (Number of Patients Reporting Adverse Events) (Knee OA) - 3 months or less- Frestedt 2008; Houpt 1999; Hughes 2002; McAlindon 2004; Noack 1994; Pujalte 1980; Reichelt
1994; Rindone 2000; Vajaradul 1981
9 randomised very no serious no serious seriousc None 91/502 94/508 RR 0.96 7 fewer per 1000 IMPORTANT
trials seriousa inconsistency indirectness (18.1%) (18.5%) (0.77 to (from 43 fewer to VERY LOW
1.20) 37 more)
Toxicity (Number of Patients Reporting Adverse Events) (Knee OA) - more than 3 months- Herrero-Beaumont 2007; Pavelka 2002; Reginster 2001; Rovati 1997
Update 2014
4 randomised seriousa no serious no serious no serious None 274/392 272/388 RR 1 (0.93 0 fewer per 1000 IMPORTANT
trials inconsistency indirectness imprecision (69.9%) (70.1%) to 1.08) (from 49 fewer to MODERATE
56 more)
Pain (Hip OA) - more than 3 months (Better indicated by lower values) )- unlicensed preparation only: Rozendaal 2008
1 randomised no serious no serious no serious no serious None 111 111 - SMD 0.03 higher IMPORTANT
trials risk of bias inconsistency indirectness imprecision (0.23 lower to HIGH
0.29 higher)
WOMAC Pain Subscale (Hip OA) - more than 3 months (Better indicated by lower values) )- unlicensed preparation only: Rozendaal 2008
1 randomised no serious no serious no serious no serious None 111 111 - SMD 0.01 lower IMPORTANT
0.25 higher)
WOMAC Function Subscale (Hip OA) - more than 3 months (Better indicated by lower values) )- unlicensed preparation only: Rozendaal 2008
0.20 higher)
WOMAC Stiffness Subscale (Hip OA) - more than 3 months (Better indicated by lower values) )- unlicensed preparation only: Rozendaal 2008
1 randomised no serious no serious no serious no serious None 111 111 - SMD 0.00 higher IMPORTANT
0.27 higher)
Toxicity (Number of Patients Reporting Adverse Events) (Hip OA) - more than 3 months - unlicensed preparation only: Rozendaal 2008
1 randomised no serious no serious no serious seriousc None 57/111 59/111 RR 0.97 16 fewer per 1000 IMPORTANT
trials risk of bias inconsistency indirectness (51.4%) (53.2%) (0.75 to (from 133 fewer to MODERATE
1.24) 128 more)

Osteoarthritis
a) Outcomes were downgraded by one increment if the weighted average number of serious methodological limitation s across studies was one, and downgraded by two increments if the
b) Outcomes were downgraded by one increment if the degree of inconsistency across studies was deemed serious (I squared 50 - 74%, or chi square p value of 0.05 or less). Outcomes
were downgraded by two increments if the degree of inconsistency was deemed very serious (I squared 75% or more. Inconsistent outcomes were therefore re-analysed using a random
effects model, rather than the default fixed effect model used initially for all outcomes. The point estimate and 95% CIs given in the grade table and forest plots are those derived from the
new random effects analysis.
c) Outcomes were downgraded by one increment if the upper or lower 95% CI crossed the lower MID or the upper or lower 95% CI crossed the upper MID. Outcomes were downgraded by
two increments if the upper CI simultaneously crossed the upper MID and the lower CI crossed the lower MID.
Table 96: Glucosamine hydrochloride and sulfate versus placebo- sensitivity analysis according to time points
2
Outcome Number of studies Effect size Heterogeneity (I , %)
Pain (pooled outcomes)- 3-6 weeks 3 (Houpt 1999; Hughes 2002; Vajaradul SMD -0.26 (-0.69, 0.18) 62
1981)
Pain (pooled outcomes)- 7-9 weeks 2 (Pujalte 1980; Rindone 2000) SMD -0.87 (-2.57, 0.082) 89
Pain (pooled outcomes)- 12 weeks 4 (Giordano 2009; Herrero-Beaumont SMD -0.21 (-0.50, 0.07) 58
Update 2014
2007; McAlindon 2004; Usha 2004)
Pain (pooled outcomes)- 20 weeks 1 (Rovati 1997) SMD -1.24 (-1.58, -0.89) -
Pain (pooled outcomes)- 24 weeks 2 (Cibere 2004; Clegg 2006) SMD -0.01 (-0.15, 0.13) -
Pain (pooled outcomes)- 2-3 years 2 (Pavelka 2002; Reginster 2001) SMD -0.10 (-0.29, 0.09) -
Pain (pooled outcomes)- total 14 SMD -0.28 (-0.49, -0.08) -
WOMAC pain- 3-6 weeks 2 (Houpt 1999; Hughes 2002) SMD -0.05 (-0.35, 0.24) -
WOMAC pain- 12 weeks 3 (Frestedt 2008; Giordano 2009; SMD 0.08 (-0.15, 0.31) 77
McAlindon 2004)
WOMAC pain- total 10 SMD -0.05 (-0.14, 0.04) 35
WOMAC stiffness- 3-6 weeks 2 (Houpt 1999; Hughes 2002) SMD -0.01 (-0.31, 0.29) 42
WOMAC stiffness- 12 weeks 2(Frestedt 2008; Giordano 2009) SMD 0.19 (-0.22, 0.60) 66
WOMAC stiffness- total 7 SMD -0.02 (-0.13, 0.09) 24
Lequesne index- 20 weeks 1 (Rovati 1997) SMD -1.28 (-1.62, -0.93) -
Lequesne index- 24 weeks 1 (Herrero-Beaumont 2007) SMD -0.36 (-0.62, -0.07) -
Lequesne index- 2-3 years 1 (Pavelka 2002) SMD -0.38 (-0.66, -0.10) -
Lequesne index- total 5 SMD -0.47 (-0.82, -0.12) 86

Osteoarthritis
2
Outcome Number of studies Effect size Heterogeneity (I , %)
OARSI responder criteria- 24 weeks 2 (Clegg 2006; Herrero- Beaumont RR 1.36 (0.78, 2.36) 84
2007)
OARSI responder criteria- total 3 RR 1.23 (0.83, 1.83) 69
Table 97: Glucosamine hydrochloride and sulfate versus placebo- sensitivity analysis according to study quality1
1
Outcome All studies Sensitivity analysis with high quality trials
Number of studies Effect size Number of studies Effect size
Pain (pooled outcomes)- short 8 SMD -0.29 (-0.57, -0.00) 2 0.05 (-0.19, 0.28)
term
Pain (pooled outcomes)- long 6 SMD -0.28 (-0.59, 0.03) 4 -0.41 (-0.91, 0.09)
Update 2014
term
Pain (pooled outcomes)- total 14 SMD -0.28 (-0.49, -0.08) 6 -0.26 (-0.63, 0.11)
WOMAC pain- short term 5 SMD 0.03 (-0.15, 0.21) 2 0.05 (-0.19, 0.28)
WOMAC pain- total 10 SMD -0.05 (-0.14, 0.04) 5 -0.09 (-0.23, 0.05)
WOMAC stiffness- short term 4 SMD 0.06 (-0.18, 0.30) 1 0.21 (-0.23, 0.66)
WOMAC stiffness- long term 3 SMD -0.04 (-0.16, 0.09) 2 -0.11 (-0.25, 0.14)
WOMAC stiffness- total 7 SMD -0.02 (-0.13, 0.09) 3 -0.05 (-0.25, 0.14)
Lequesne index- short term 2 SMD -0.02 (-0.40, 0.00) 1 -0.20 (-0.45, 0.05)
Lequesne index- total 5 SMD -0.47 (-0.82, -0.12) 4 -0.54 (-0.96, -0.12)
OARSI responder criteria- long 2 RR 1.36 (0.78, 2.38) 1 1.87 (1.21, 2.91)
term
OARSI responder criteria- total 3 RR 1.23 (0.83, 1.83) 2 1.37 (0.69, 2.73)
1
High quality trials were trials where all criteria for quality assessment in Cochrane were met. These criteria were: appropriate description of allocation concealment, study described as
“randomised”; method of randomisation described and appropriate; study described as “double blind”; method of blinding described and appropriate; number and reason for withdrawals
in each group described.

Osteoarthritis
Table 98: Glucosamine hydrochloride and sulfate (licensed and unlicensed) versus placebo- sensitivity analysis with Rovati 1997 removed
Outcome All studies Sensitivity analysis with Rovati 1997 removed
Pain – long term 6 SMD -0.28 (-0.59, 0.03) 7 SMD -0.08 (-0.19, 0.22)
Pain – Total 14 SMD -0.28 (-0.49, -0.08) 13 SMD -0.16 (-0.30, -0.02)
Lequesne index- long term 3 SMD -0.66 (-1.21, -0.11) 2 SMD -0.36 (-0.56, -0.17)
Lequesne index- total 5 SMD -0.47 (-0.82, -0.12) 4 SMD -0.28 (-0.42, -0.14)
Toxicity- long term 4 RR 1.0 (0.93, 1.08) 3 RR 1.03 (0.96, 1.10)
Toxicity- total 13 RR 0.99 (0.91, 1.07) 12 RR 1.01 (0.93, 1.09)
Table 99: Glucosamine hydrochloride and sulfate versus NSAIDs (knee)
Update 2014
Glucosamine versus NSAIDs Quality Importance

No of Other (piroxicam, ibuprofen, Relative
Design Risk of bias Inconsistency Indirectness Imprecision Control Absolute
studies considerations celecoxib)- subgroup by joint (95% CI)
type and length of follow up)
Pain (Knee OA) (Better indicated by lower values): Qiu 1998; Lopes-Vas 1982; Clegg 2006; Rovati 1997
4 randomised very seriousa very seriousb no serious seriousc None 501 496 - SMD 0.27 CRITICAL
trials indirectness lower (0.65 VERY LOW
lower to 0.11
higher)
Pain (Knee OA) - 3 months or less (Better indicated by lower values): Qiu 1998; Lopes-Vas 1982- unlicensed preparation only
2 randomised very seriousa seriousb no serious seriousc None 105 101 - SMD 0.36 CRITICAL
lower to 0.1
higher)
Pain (Knee OA) - more than 3 months (Better indicated by lower values): Clegg 2006; Rovati 1997
2 randomised seriousa very seriousb no serious seriousc None 396 395 - SMD 0.2 CRITICAL
lower to 0.45
higher)
Lequesne Index (Knee OA) (Better indicated by lower values): Muller-FassBender1994; Rovati 1997
2 randomised no serious very seriousb no serious seriousc None 173 172 - SMD 0.36 CRITICAL
trials risk of bias indirectness lower (1.07 VERY LOW
lower to 0.35
higher)

Osteoarthritis
Lequesne Index (Knee OA) - 3 months or less (Better indicated by lower values) )- unlicensed preparation only Muller-FassBender1994
1 randomised no serious no serious no serious no serious None 94 95 - SMD 0 CRITICAL
trials risk of bias inconsistency indirectness imprecision higher (0.29 HIGH
lower to 0.29
higher)
Lequesne Index (Knee OA) - more than 3 months (Better indicated by lower values)- Rovati 1997
1 randomised no serious no serious no serious seriousc None 79 77 - SMD 0.73 CRITICAL
trials risk of bias inconsistency indirectness lower (1.05 to MODERATE
0.4 lower)
Patient Global Assessment (Knee OA) - more than 3 months (Better indicated by higher values) )- unlicensed preparation only Clegg 2006
1 randomised seriousa no serious no serious very seriousc None 317 318 - SMD 0.07 IMPORTANT
trials inconsistency indirectness higher (0.08 VERY LOW
lower to 0.23
higher)
Toxicity (Number of Patients Reporting Adverse Events) (Knee OA) Muller-FassBender1994; Lopes-Vas 1982; Qiu 1998; Rovati 1997
4 randomised seriousa no serious no serious no serious None 25/285 90/295 RR 0.29 217 fewer IMPORTANT
trials inconsistency indirectness imprecision (8.8%) (30.5%) (0.19 to per 1000 MODERATE
0.44) (from 171
fewer to 247
Update 2014
fewer)
Toxicity (Number of Patients Reporting Adverse Events) (Knee OA) - 3 months or less- unlicensed preparation only Muller-FassBender1994; Lopes-Vas 1982; Qiu 1998
3 randomised seriousa no serious no serious no serious None 13/206 54/209 RR 0.24 196 fewer IMPORTANT
trials inconsistency indirectness imprecision (6.3%) (25.8%) (0.14 to per 1000 MODERATE
0.43) (from 147
fewer to 222
fewer)
Toxicity (Number of Patients Reporting Adverse Events) (Knee OA) - more than 3 months Rovati 1997
1 randomised no serious no serious no serious no serious None 12/79 36/86 RR 0.36 268 fewer IMPORTANT
trials risk of bias inconsistency indirectness imprecision (15.2%) (41.9%) (0.2 to per 1000 HIGH
0.65) (from 147
fewer to 335
fewer)
b) Outcomes were downgraded by one increment if the degree of inconsistency across studies was deemed serious (I squared 50 - 74%, or chi square p value of 0.05 or less). Outcomes were
downgraded by two increments if the degree of inconsistency was deemed very serious (I squared 75% or more. Inconsistent outcomes were therefore re-analysed using a random effects
model, rather than the default fixed effect model used initially for all outcomes. The point estimate and 95% CIs given in the grade table and forest plots are those derived from the new random
effects analysis.
c) Outcomes were downgraded by one increment if the upper or lower 95% CI crossed the lower MID or the upper or lower 95% CI crossed the upper MID. Outcomes were downgraded by two

Osteoarthritis
Table 100: Glucosamine hydrochloride and sulfate versus NSAIDs- sensitivity analysis according to treatment duration
2
Outcome Number of studies Effect size Heterogeniety (I , %)
Pain (pooled outcomes)- 3-6 weeks 1 (Qiu 1998) SMD -0.20 (-0.50, 0.11) -
267
Pain (pooled outcomes)- 7-9 weeks 1 (Lopes-Vas 1982 ) SMD -0.71 (-1.36, -0.05) -
Pain (pooled outcomes)- 24 weeks 1 (Clegg 2006) SMD 0.12 (-0.65, 0.11) -
Lequesne index- 3-6 weeks 1 (Rovati 1997) SMD 0.00 (-0.29, 0.29) -
Lequesne index-20 weeks 1 (Clegg 2006) SMD -0.73 (-1.05, -0.40) -
Update 2014
Table 101: Glucosamine hydrochloride and sulfate versus NSAIDs- sensitivity analysis according to study quality1
1
Outcome All studies Sensitivity analysis with high quality trials
Pain (pooled outcomes)- short 2 SMD -0.36 (-0.83, 0.10) none -
term
Pain (pooled outcomes)- long 2 SMD -0.20 (-0.85, 0.45) 1 (Rovati 1997) SMD -0.54 (-0.86, -0.22)
term
Pain (pooled outcomes)- total 4 SMD -0.27 (-0.65, 0.11) 1 (Rovati 1997) SMD -0.54 (-0.86, -0.22)
1
High quality trials were thosewhere all criteria for quality assessment in Cochrane were met. These criteria were: appropriate description of allocation concealment, study described as
* Lequesne index had unexplained heterogeneity, but both trials in the analysis were high quality and therefore there was no change in the effect size when sensitivity analysis undertaken.

Osteoarthritis
Table 102: Licensed glucosamine sulfate versus placebo (Knee)

Licensed glucosamine Quality Importance

No of Risk of Other versus placebo- subgroup Relative
studies bias considerations by joint type and length of (95% CI)
follow up
Pain (pooled measures) (Knee OA) (Better indicated by lower values) Pujalte 1980; Herrero-Beaumont 2007; Pavelka 2002; Reginster 2001; Rovati 1997
trials indirectness (1.06 to 0.1 VERY LOW
lower)
Pain (pooled measures) (Knee OA) - 3 months or less (Better indicated by lower values) Pujalte 1980
trials inconsistency indirectness imprecision (2.89 to 0.74 MODERATE
lower)
Pain (pooled measures) (Knee OA) - more than 3 months treatment (Better indicated by lower values) Herrero-Beaumont 2007; Pavelka 2002; Reginster 2001; Rovati 1997
trials indirectness (0.9 lower to 0.05 VERY LOW
higher)
Update 2014
WOMAC Pain Subscale (Knee OA) - more than 3 months treatment (Better indicated by lower values) Herrero-Beaumont 2007; Pavelka 2002; Reginster 2001
3 randomised seriousa no serious no serious no serious None 313 311 - SMD 0.17 lower MODERATE CRITICAL
trials inconsistency indirectness imprecision (0.32 to 0.01
lower)
WOMAC Function Subscale (Knee OA) - more than 3 months treatment (Better indicated by lower values) Herrero-Beaumont 2007; Pavelka 2002; Reginster 2001
lower)
WOMAC Stiffness Subscale (Knee OA) - more than 3 months (Better indicated by lower values) Pavelka 2002
1 randomised no serious no serious no serious seriousc None 101 101 - SMD 0.22 lower MODERATE CRITICAL
trials risk of bias inconsistency indirectness (0.50 lower to
0.06 higher)
Lequesne Index (Knee OA) (Better indicated by lower values) Noack 1994; Reichelt 1994; Herrero-Beaumont 2007; Pavelka 2002; Rovati 1997
5 randomised seriousa very seriousb no serious seriousc None 479 472 - SMD 0.47 lower VERY LOW CRITICAL
trials indirectness (0.82 to 0.12
lower)
Lequesne Index (Knee OA) - 3 months or less (Better indicated by lower values) Noack 1994; Reichelt 1994
trials inconsistency indirectness imprecision (0.4 lower to 0 MODERATE
higher)
Lequesne Index (Knee OA) - more than 3 months (Better indicated by lower values) Herrero-Beaumont 2007; Pavelka 2002; Rovati 1997
3 randomised no serious very seriousb no serious seriousc None 286 282 - SMD 0.66 lower CRITICAL
trials risk of bias indirectness (1.21 to 0.11 VERY LOW
lower)

Osteoarthritis
Minimum Joint Space Width (Knee OA) -more than 3 months (Better indicated by lower values) Pavelka 2002, Reginster 2001
2 randomised seriousa no serious no serious seriousc None 207 207 - SMD 0.24 higher IMPORTANT
higher)
Mean Joint Space Width (Knee OA) - more than 3 months (Better indicated by lower values) Reginster 2001
1 randomised seriousa no serious no serious no serious None 106 106 - SMD 0.07 higher IMPORTANT
0.34 higher)
Osteoarthritis Research Society International Responder Criteria (OARSI) (Knee OA) - more than 3 months- Herrero-Beaumont 2007
1 randomised no serious no serious no serious seriousc None 42/106 22/104 RR 1.87 184 more per IMPORTANT
trials risk of bias inconsistency indirectness (39.6%) (21.2%) (1.21 to 1000 (from 44 MODERATE
2.91) more to 404
more)
Toxicity (Number of Patients Reporting Adverse Events) (Knee OA)- Noack 1994; Reichelt 1994; Pujalte 1980; Herrero-Beaumont 2007; Pavelka 2002; Rovati 1997; Reginster 2001
7 randomised seriousa no serious no serious no serious None 287/609 293/602 RR 0.97 15 fewer per IMPORTANT
Update 2014
trials inconsistency indirectness imprecision (47.1%) (48.7%) (0.9 to 1000 (from 49 MODERATE
1.05) fewer to 24 more)
Toxicity (Number of Patients Reporting Adverse Events) (Knee OA) - 3 months or less- Noack 1994; Reichelt 1994; Pujalte 1980
3 randomised very no serious no serious seriousc None 13/217 21/214 RR 0.62 37 fewer per IMPORTANT
trials seriousa inconsistency indirectness (6%) (9.8%) (0.32 to 1000 (from 67 VERY LOW
1.19) fewer to 19 more)
Toxicity (Number of Patients Reporting Adverse Events) (Knee OA) - more than 3 months- Herrero-Beaumont 2007; Pavelka 2002; Rovati 1997; Reginster 2001;
4 randomised seriousa no serious no serious no serious None 274/392 272/388 RR 1 (0.93 0 fewer per 1000 IMPORTANT
trials inconsistency indirectness imprecision (69.9%) (70.1%) to 1.08) (from 49 fewer to MODERATE
56 more)
effects analysis.

Osteoarthritis
Table 103: Licensed glucosamine sulfate versus placebo- sensitivity analysis according to treatment duration
Outcome Number of studies Effect size Heterogeneity (I2, %)
Pain (pooled outcomes)- 7-9 weeks 1 (Pujalte 1980) SMD -1.81 (-2.89, -0.74) -
Pain (pooled outcomes)- 24 weeks 1 (Herrero- Beaumont 2007) SMD -0.30 (-0.57, -0.03) -
Pain (pooled outcomes)- 2-3 years 2 (Pavelka 2002, Reginster 2001) SMD -0.10 (-0.29, 0.09) -
Pain (pooled outcomes)- total 5 SMD -0.58 (-1.06, -0.10) 90
Lequesne index- 3-6 weeks 1 (Noack ) SMD -0.20 (-0.45, 0.05) -
Lequesne index- 20 weeks 1 (Rovati 1997) SMD -1.28 (-1.62, -0.93) -
Lequesne index- 24 weeks 1 (Herrero- Beaumont 2007) SMD -0.35 (-0.62, -0.07) -
Lequesne index- 2-3 years 1 (Pavelka 2002) SMD -0.38 (-0.66, -0.10) -
Lequesne index- total 4 SMD -0.54 (-0396, -0.12) 89
Update 2014
Table 104: Licensed glucosamine sulfate versus placebo- sensitivity analysis according to study quality1
All studies
High quality studies
Outcome Number of studies Effect size Number of studies Effect size
Pain (pooled outcomes)- 3 1 (Pujalte 1980) SMD -1.81 (-2.89, -0.74) 0 -
months or less
Pain (pooled outcomes)- more 4 (Herrero Beaumont2007; SMD -0.43 (-0.90, 0.05) 3 (Herrero Beaumont2007; SMD -0.55 (-1.17, 0.08)
than 3 months Pavelka 2002; Reginster 2001; Pavelka 2002; Rovati 1997)
Rovati 1997)
Pain (pooled outcomes)- total 5 (Pujalte 1980; Herrero SMD -0.58 (-1.06, -0.10) 3 (Herrero Beaumont2007; SMD -0.55 (-1.17, 0.08)
Beaumont2007; Pavelka 2002; Pavelka 2002; Rovati 1997)
Reginster 2001; Rovati 1997)
Lequesne index-3 months or 2 (Noack 1994; Reichelt 1994) SMD -0.20 (-0.40, 0.00) 1 (Noack 1994) SMD -0.20 (-0.45, 0.05)
less
Lequesne index- more than 3 3 (Herrero-Beaumont 2007; SMD -0.66 (-1.21, -0.11) 3 (Herrero-Beaumont 2007; SMD -0.66 (-1.21, -0.11)
months Pavelka 2002; Rovati 1997) Pavelka 2002; Rovati 1997)
Lequesne index-total 5 (Noack 1994; Reichelt 1994; SMD -0.47 (-0.82, -0.12) 4 (Noack 1994;Herrero- SMD -0.54 (-0.96, -0.12)

Osteoarthritis
All studies
Outcome High quality studies
Herrero-Beaumont 2007; Beaumont 2007; Pavelka 2002;
Pavelka 2002; Rovati 1997) Rovati 1997)
1
High quality trials were those where all criteria for quality assessment in Cochrane were met. These criteria were: appropriate description of allocation concealment, study described as
Table 105: Licensed glucosamine sulfate formulations versus placebo- sensitivity analysis with Rovati 1997 removed
Outcome All studies Sensitivity analysis with Rovati 1997 removed
Pain - long term 4 SMD -0.43 (-0.90, 0.05) 3 SMD -0.17 (-0.32, -0.01)
Pain – Total 5 SMD -0.58 (-1.06, -0.10) 4 SMD -0.29 (-0.61, 0.03)
Update 2014
Lequesne index- long term 3 SMD -0.66 (-1.21, -0.11) 2 SMD -0.36 (-0.56, -0.17)
Lequesne index- total 5 SMD -0.47 (-0.82, -0.12) 4 SMD -0.28 (-0.42, -0.14)
Toxicity- long term 4 RR 1.00 (0.93, 1.08) 3 RR 1.03 (0.96, 1.10)
Toxicity- total 7 RR 0.97 (0.90, 1.05) 6 RR 1.00 (0.92, 1.07)
Table 106: Licensed glucosamine versus placebo- Bruyere (2009) post-hoc analysis of long term joint replacement outcome
Importanc
Quality
No of Risk of Imprecisio Other Glucosamin Placeb Relative e
Design Inconsistency Indirectness Absolute
studies bias n considerations e o (95% CI)
number of people with TKR: Bruyere 2009
1 randomised very no serious no serious seriousb None 9/144 19/131 RR 0.43 (0.2 83 fewer per 1000 (from 12 VERY IMPORTAN
trials seriousa inconsistency indirectness (6.3%) (14.5%) to 0.92) fewer to 116 fewer) LOW T
a) Post hoc analysis of Pavelka 2002 and Reginster 2001 studies. 19% of patients lost to follow up. Retrospective information on medication and other intervention history not available during
the follow up period.
b) Outcomes were downgraded by one increment if the upper or lower 95% CI crossed the lower MID or the upper or lower 95% CI crossed the upper MID. Outcomes were downgraded by two

Osteoarthritis
Table 107: Licensed glucosamine sulfate versus NSAIDs (Knee)

Licensed glucosamine versus Quality Importance

No of Risk of Other NSAIDs (piroxicam, ibuprofen, Relative
studies bias considerations celecoxib)- subgroup by joint (95% CI)
type and length of follow up)
Pain (Knee OA) - more than 3 months (Better indicated by lower values)- Rovati 1997
1 randomised no no serious no serious seriousa None 79 77 - SMD 0.54 lower CRITICAL
trials serious inconsistency indirectness (0.86 to 0.22 MODERATE
risk of lower)
bias
Lequesne Index (Knee OA) - more than 3 months (Better indicated by lower values)- Rovati 1997
1 randomised no no serious no serious seriousa None 79 77 - SMD 0.73 lower CRITICAL
trials serious inconsistency indirectness (1.05 to 0.40 MODERATE
risk of lower)
bias
Toxicity (Number of Patients Reporting Adverse Events) (Knee OA) - more than 3 months- Rovati 1997
1 randomised no no serious no serious no serious None 12/79 36/86 RR 0.36 268 fewer per IMPORTANT
Update 2014
trials serious inconsistency indirectness imprecision (15.2%) (41.9%) (0.2 to 1000 (from 147 HIGH
risk of 0.65) fewer to 335
bias fewer)
a) Outcomes were downgraded by one increment if the upper or lower 95% CI crossed the lower MID or the upper or lower 95% CI crossed the upper MID. Outcomes were downgraded by two
Table 108: Licensed glucosamine sulfate versus paracetamol (Knee)

Glucosamine versus Quality Importance

No of Risk of Other paracetamol- subgroup by Relative
studies bias considerations joint type and length of (95% CI)
follow up
WOMAC pain - more than 3 months (Better indicated by lower values) Herrero-Beaumont 2007
1 randomised no serious no serious no serious seriousa None 106 108 - SMD 0.33 CRITICAL
trials risk of inconsistency indirectness lower (0.60 to MODERATE
bias 0.06 lower)
WOMAC function - more than 3 months (Better indicated by lower values) Herrero-Beaumont 2007
1 randomised no serious no serious no serious no serious None 106 108 - SMD 0 higher CRITICAL
trials risk of inconsistency indirectness imprecision (0.27 lower to HIGH
bias 0.27 higher)
Lequesne Index - more than 3 months (Better indicated by lower values) Herrero-Beaumont 2007
1 randomised no serious no serious no serious no serious None 106 108 - SMD 0 higher CRITICAL
trials risk of inconsistency indirectness imprecision (0.27 lower to HIGH

Osteoarthritis
bias 0.27 higher)

OARSI responder criteria - more than 3 months Herrero-Beaumont 2007
1 randomised no serious no serious no serious seriousa None 42/106 36/108 RR 1.19 63 more per IMPORTANT
trials risk of inconsistency indirectness (39.6%) (33.3%) (0.83 to 1000 (from 57 MODERATE
bias 1.7) fewer to 233
more)
Table 109: Licenced glucosamine sulfate versus paracetamol (Hand)

Quality Importance
No of Risk of Other Relative
Design Inconsistencyb Indirectness Imprecisionb Glucosamine sulfate Paracetamol Absolute
studies bias considerations (95% CI)
100mm VAS Pain at 6 weeks (better indicated by lower scores): Patru 2012
1 randomised very - no serious - None 25 25 - “GS decreased CRITICAL
trials seriousa indirectness pain by 28%, LOW
paracetamol by
24.2%”
Update 2014
Hand function test: Moburg pick up test (MPUT) at 6 weeks (Better indicated by lower scores): Patru 2012
1 randomised very - no serious - None 25 25 - “GS (12.6s) CRITICAL
trials seriousa indirectness significantly LOW
superior to
paracetamol
(15.6) in
improving hand
function”
Quality of life: SF-36 at 6 weeks: Patru 2012
1 randomised very - no serious - None 106 108 - “The SF-36 IMPORTANT
trials seriousa indirectness scores were LOW
significantly
improved in the
GS group for
physical function,
role physical,
mental health and
role emotional
subscales”
a) RCT conference abstract with only limited methodological information; randomisation, allocation concealment, and blinding unclear
b) Inconsistency and imprecision could not be assessed as the data could not be meta-analysed

Osteoarthritis
Table 110: Chondroitin versus placebo (knee)

Quality Importance
OA-Knee-
No of Other Relative
Design Risk of bias Inconsistency Indirectness Imprecision Chondroitin v Control Absolute
studies considerations (95% CI)
Placebo
Pain VAS- pooled (Better indicated by lower values): Bourgeois 1998; Kerzberg 1987; Moller 2010; Pavelka 1999; Bucsi 1998; Conrozier 1992; Kahan 2009;; L'Hirondel 1992; Malaise 1999;
Mazierer 1992; Mazieres 2007; Morreale 1996; Railhac 2012; Rovetta 1991; Uebelhart 1998; Wildi 2011; Zegels 2013
a b c
17 randomised serious very serious no serious serious None 1206 1129 - SMD 0.75 lower CRITICAL
trials indirectness (1.03 to 0.48 lower) VERY LOW
Pain VAS - Pain VAS- Time points less than 3 months (Better indicated by lower values): Bourgeois 1998; Kerzberg 1987; Moller 2010;Pavelka 1999
4 randomised very no serious no serious no serious None 221 144 - SMD 0.87 lower
a CRITICAL
trials serious inconsistency indirectness imprecision (1.19 to 0.54 lower) LOW
Pain VAS - Pain VAS- Time points greater than 3 months (Better indicated by lower values): Bucsi 1998; Conrozier 1992; Kahan 2009; L'Hirondel 1992; Malaise 1999; Mazieres 1992;
Mazieres 2007 ;Morreale 1996;Rovetta 1991;Uebelhart 1998; Wildi 2011; Railhac 2012; Zegels 2013
a b c
Update 2014
13 randomised serious very serious no serious serious None 985 985 - SMD 0.72 lower
CRITICAL
Pain WOMAC- Time points greater than 3 months (Better indicated by lower values): Clegg 2006; Wildi 2011; Kahan 2009; Michel 2005
a
4 randomised serious no serious no serious no serious None 0 - - MD 0.04 lower
trials inconsistency indirectness imprecision (0.19 lower to 0.11 MODERATE CRITICAL
higher)
WOMAC function- Time points greater than 3 months (Better indicated by lower values): Clegg 2006
SMD 0.01 higher
randomised no serious no serious no serious no serious
1 None 318 313 - (0.15 lower to 0.17 CRITICAL
trials risk of bias inconsistency indirectness imprecision HIGH
higher)
WOMAC stiffness- Time points greater than 3 months (Better indicated by lower values): Clegg 2006
SMD 0.1 higher
higher)
Change in minimum joint space width loss- Time points greater than 3 months (Better indicated by higher values): Uebelhart 1998; Kahan 2009; Michel 2005
a
3 randomised serious no serious no serious no serious None 473 475 - SMD 0.31 higher
trials inconsistency indirectness imprecision (0.15 to 0.46 MODERATE IMPORANT
higher)
OMERACT-OARSI response- Time points greater than 3 months: Clegg 2006; Mazieres 2007
RR 1.15 85 more per 1000
randomised a no serious no serious no serious 306/471 264/467 IMPORTAN
2 serious None (1.04 to (from 23 more to
trials inconsistency indirectness imprecision (65%) (56.5%) MODERATE T
1.27) 153 more)

Osteoarthritis
SF-36 Physical component- 3 months (Better indicated by higher values): Moller 2010
SMD 0.34 higher
randomised a no serious no serious c IMPORTAN
1 serious serious None 60 56 - (0.03 lower to 0.7
trials inconsistency indirectness LOW T
higher)
SF-36 Mental component-3 months (Better indicated by higher values): Moller 2010
SMD 0.07 lower
randomised a no serious no serious no serious IMPORTAN
1 serious None 60 56 - (0.43 lower to 0.3
trials inconsistency indirectness imprecision MODERATE T
higher)
SF-12 Physical component- Time points greater than 3 months (Better indicated by higher values): Mazieres 2007
SMD 0.21 higher
higher)
SF-12-Mental component- Time points greater than 3 months (Better indicated by higher values) Mazieres 2007
SMD 0.08 higher
higher)
Patient's global assessment- Time points greater than 3 months (Better indicated by higher values): Clegg 2006; Mazieres 2007
Update 2014
SMD 0.09 higher
higher)
Adverse events: Bourgeois 1998;Bucsi 1998 ; Kahan 2009; Mazieres 1992; Mazieres 2007; Moller 2010; Morreale 1996; Rovetta 1991; Wildi 2011; Clegg 2006; Michel 2005; Railhac 2012
a
12 randomised serious no serious no serious no serious None 168/1311 159/126 RR 0.98 3 fewer per 1000 IMPORTAN
trials inconsistency indirectness imprecision (12.8%) 7 (0.81 to (from 24 fewer to MODERATE T
(12.5%) 1.18) 23 more)
Adverse events - Adverse events- Time points less than 3 months: Bourgeois 1998; Moller 2010
c
2 randomised very no serious no serious serious None 47/143 43/100 RR 0.86 60 fewer per 1000 IMPORTAN
a
trials serious inconsistency indirectness (32.9%) (43%) (0.63 to (from 159 fewer to VERY LOW T
1.17) 73 more)
Adverse events - Adverse events- Time points greater than 3 months: Bucsi 1998 ; Kahan 2009; Mazieres 1992; Mazieres 2007; Morreale 1996; Rovetta 1991; Wildi 2011; Clegg 2006;
Michel 2005; Railhac 2012
a c
10 randomised serious no serious no serious serious None 121/1168 116/116 RR 1.03 3 more per 1000 IMPORTAN
trials inconsistency indirectness (10.4%) 7 (0.82 to (from 18 fewer to LOW T
(9.9%) 1.29) 29 more)

Osteoarthritis
effects analysis. Sensitivity analysis with different time points and high quality trials undertaken
Table 111: Chondroitin versus placebo (Hip)

Qualit Importanc
y e
OA- Hip-
Design Inconsistency Indirectness Imprecision Chondroitin v Control Absolute
Placebo
Pain VAS- Time points greater than 3 months (Better indicated by lower values): Conrozier 19988
Update 2014
randomised very no serious no serious no serious SMD 0.60 lower (0.99 to
1 a None 52 52 - CRITICAL
trials serious inconsistency indirectness imprecision 0.20 lower) LOW
Table 112: Chondroitin versus placebo (Hand)

Quality Importance
OA- Hand
Design Risk of bias Inconsistency Indirectness Imprecision Chondroitin v Control Absolute
Placebo
Pain VAS- Time points greater than 3 months (Better indicated by lower values): Gabay 2011
SMD 0.29 lower
higher)
FIHOA score- Time points greater than 3 months (Better indicated by lower values): Gabay 2011

Osteoarthritis
trials risk of bias inconsistency indirectness imprecision (0.58 lower to 0.09 HIGH
higher)
Adverse events- Time points greater than 3 months: Gabay 2011
8 more per 1000
randomised no serious no serious no serious a 34/80 34/82 RR 1.02 (0.71
1 very serious None (from 120 fewer to IMPORTANT
trials risk of bias inconsistency indirectness (42.5%) (41.5%) to 1.47) LOW
195 more)
Table 113: Chondroitin versus NSAIDs (knee)

Quality Importance
No of Other OA Knee- Chondroitin v Contro Relative
Design Risk of bias Inconsistency Indirectness Imprecision Absolute
studies considerations NSAID(Celecoxib) l (95% CI)
Pain WOMAC- Time points greater than 3 months (Better indicated by lower values): Clegg 2006
SMD 0.14 higher
Update 2014
higher)
WOMAC function- Time points greater than 3 months (Better indicated by lower values): Clegg 2006
SMD 0.11 higher
higher)
WOMAC stiffness- Time points greater than 3 months (Better indicated by lower values): Clegg 2006
randomised no serious no serious no serious no serious SMD 0.1 higher (0.05
1 None 318 318 - HIGH CRITICAL
trials risk of bias inconsistency indirectness imprecision lower to 0.26 higher)
OMERACT-OARSI response- Time points greater than 3 months: Clegg 2006
214/31
RR 0.94 40 fewer per 1000
randomised no serious no serious no serious no serious 202/318 8
1 None (0.84 to (from 108 fewer to IMPORTANT
trials risk of bias inconsistency indirectness imprecision (63.5%) (67.3% HIGH
1.06) 40 more)
)
Patient's global assessment of disease status- Time points greater than 3 months (Better indicated by higher values): Clegg 2006
SMD 0.06 higher
1 None 318 318 - (0.09 lower to 0.22 IMPORTANT
higher)
Number of patients withdrawing due to adverse events- Time points greater than 3 months: Clegg 2006

Osteoarthritis
RR 2.86 41 more per 1000

randomised no serious no serious no serious a 20/318 7/318
1 serious None (1.23 to (from 5 more to 125 MODERA IMPORTANT
trials risk of bias inconsistency indirectness (6.3%) (2.2%)
6.66) more) TE
Table 114: Chondroitin versus placebo: Sensitivity analysis on the basis of study quality
*
All studies Sensitivity analysis with high quality trials
Outcome
Number of Effect size Number of studies Effect size
studies
229
Pain VAS (pooled) 15 SMD 0.82 lower (1.13 to 0.51 lower) 1 SMD 0.03 lower (0.18 lower to 0.13 higher)
78,229,310
Pain WOMAC 4 MD 0.04 lower (0.19 lower to 0.11 3 MD 0.04 lower (0.19 lower to 0.11 higher)
higher)
Update 2014
High quality trials were identified as those which presented a low risk of bias. These were Kahan2006, Clegg2006, Michel2005 and Gabay 2011.
Table 115: Chondroitin versus placebo: Sensitivity analysis based on time points of observation
All studies Sensitivity analysis based on time points of observation
Outcome
Number of Effect size Number of studies Effect size
studies
Pain VAS(pooled) 15 SMD 0.82 lower (1.13 to 0.51 lower)
Pain VAS- time points less than 3 4 SMD 0.87 lower (1.19 to 0.54 lower
months
238
Pain VAS- 6 weeks 1 SMD 0.99 lower (2.01 lower to 0.04 higher)
43,316,345
Pain VAS- 3 months 3 SMD 0.86 lower (1.24 to 0.48 lower)
Pain VAS- time points greater than 11 SMD 0.8 lower (1.19 to 0.42 lower
3 months
53,85,250,286,287,317,492
Pain VAS- 6 months 7 SMD 0.80 lower (1.31 to 0.28 lower)
229,275,393,465
Pain VAS- 1 year 4 SMD 0.83 lower (1.54 to 0.12 lower)

Osteoarthritis
Table 9: Glucosamine sulfate or glucosamine hydrochloride and chondroitin sulfate versus placebo (knee)
Importanc
Quality
No of Risk of Other Glucosamine+Chondroiti Placeb Relative e
Design Inconsistency Indirectness Imprecision Absolute
studies bias considerations n o (95% CI)
WOMAC Pain - More than 3 months treatment (Better indicated by lower values): Clegg 2006; Messier 2007
0.04 higher)
WOMAC function - More than 3 months treatment (Better indicated by lower values): Clegg 2006; Messier 2007
trials seriousa inconsistency indirectness imprecision (0.29 lower to 0 LOW
higher)
WOMAC Stiffness - More than 3 months treatment (Better indicated by lower values): Clegg 2006
1 randomised very no serious no serious no serious None 317 313 - SMD 0.09 lower LOW CRITICAL
trials seriousa inconsistency indirectness imprecision (0.25 lower to
Update 2014
0.07 higher)
189
Patient global assessment - More than 3 months treatment (Better indicated by lower values): Clegg 2006
1 randomised very no serious no serious no serious None 317 313 - SMD 0.07 lower IMPORTAN
trials seriousa inconsistency indirectness imprecision (0.22 lower to LOW T
0.09 higher)
OARSI responder criteria - More than 3 months treatment: Clegg 2006
1 randomised very no serious no serious seriousb None 208/317 178/313 RR 1.15 85 more per 1000 IMPORTAN
trials seriousa inconsistency indirectness (65.6%) (56.9%) (1.02 to (from 11 more to VERY LOW T
1.31) 176 more)
Lequesne Index- more than 3 months treatment (Better indicated by lower values): Das 2000
1 randomised seriousa no serious no serious seriousb None 46 47 - SMD 0.36 lower IMPORTAN
trials inconsistency indirectness (0.77 lower to LOW T
0.06 higher)
VAS pain- less than 3 months (Better indicated by lower values): Cohen 2003
1 randomised no serious no serious no serious seriousb None 30 29 - SMD 0.68 lower IMPORTAN
trials risk of bias inconsistency indirectness (1.21 to 0.16 MODERAT T
lower) E
SF36- physical health- less than 3 months (Better indicated by higher values): Cohen 2003
1 randomised no serious no serious no serious very seriousb None 30 29 - SMD 3.10 lower IMPORTAN
trials risk of bias inconsistency indirectness (8.04 lower to LOW T
1.84 higher)
SF36- Mental Health- less than 3 months (Better indicated by higher values): Cohen 2003
Osteoarthritis
1 randomised no serious no serious no serious seriousb None 30 29 - SMD 3.90 higher
IMPORTAN
trials risk of bias inconsistency indirectness (0.27 to 7.53 MODERAT
T
higher) E
Table 116: Glucosamine sulfate or glucosamine hydrochloride and chondroitin sulfate versus NSAIDs (Knee)
Quality Importance
No of Risk of Other Glucosamine+chondroiti Relative
Design Inconsistency Indirectness Imprecision NSAID Absolute
studies bias considerations n (95% CI)
WOMAC Pain- more than 3 months treatment (Better indicated by lower values): Clegg 2006
Update 2014
1 randomised very no serious no serious no serious None 317 318 - SMD 0.02 higher CRITICAL
0.18 higher)
190
WOMAC function- more than 3 months treatment (Better indicated by lower values): Clegg 2006
0.13 higher)
WOMAC Stiffness- more than 3 months treatment (Better indicated by lower values): Clegg 2006
0.15 higher)
Patient Global Assessment- more than 3 months treatment (Better indicated by higher values): Clegg 2006
1 randomised very no serious no serious no serious None 317 318 - SMD 0.03 lower IMPORTANT
0.12 higher)
OARSI responder criteria- more than 3 months treatment: Clegg 2006
1 randomised very no serious no serious no serious none 208/317 214/31 RR 0.98 13 fewer per LOW IMPORTANT
trials seriousa inconsistency indirectness imprecision (65.6%) 8 (0.87 to 1000 (from 87
(67.3%) 1.09) fewer to 61
more)
concealment, the lack of blinding, inadequate allowance for drop-outs in the analysis, selective outcome reporting or unadjusted baseline inequality
Osteoarthritis
Update 2014
Evidence from CG59:
 Published literature
No studies were found comparing glucosamine and chondroitin alone or in compound form with the
relevant comparators.
 Original analysis
An original cost effectiveness analysis was conducted for CG59 using five placebo controlled RCTs
78,288,310,344,375
(included in the original guideline review) comparing glucosamine and chondroitin
alone or in compound form versus placebo. WOMAC scores were taken from the RCTs and mapped
onto EQ-5D using the formula from Barton 200822. Only direct costs of the interventions were
considered, assuming one GP appointment. Placebo was assumed to have no costs.
A summary of this CG59 analysis can be found in Appendix M.
Evidence statements have not been drafted for the CG59 analysis as this has not been updated in this
Update 2014
guideline update, and more weight was placed by the GDG on cost effectiveness and clinical
evidence from the update guideline.
Evidence from update guideline:
Three studies were identified from the update search that included the relevant interventions and
comparisons 410, 39, 52.
Two studies looked at the cost-effectiveness of glucosamine sulfate: one study compared
glucosamine with current care 39, this was a decision analytic model with a lifetime horizon, as well as
being a UK study part of a health technology assessment. The other study 410 compared glucosamine
with paracetamol and also with placebo, this was a Spanish study with an RCT design and a 6 month
time horizon.
One study by Bruyere (2009)52 compared chondroitin sulfate with placebo. The study had an RCT
design with a time horizon of 24 months, and was from a European perspective.
These are summarised in the economic evidence profile below (Table 117 and Table 118). See also
the study selection flowchart in appendix E and study evidence tables in appendix H.
Osteoarthritis
Table 117: Economic evidence profile: Glucosamine sulfate versus other treatments
Incremental
Incremental effects Incremental
cost per (QALYs) per cost per QALY
Study Applicability Limitations Other comments patient patient gained Uncertainty
Scholtissen Partially Potentially Comparator = paracetamol - £8.92 0.01 Dominant PSA results show that at a
410 (a)
2010 applicable serious threshold of £20,000, there is an
(b)
limitations Patient data taken from the 80% probability that Glucosamine
GUIDE study .
185 is cost-effective compared with
paracetamol.
Scholtissen Partially Potentially Comparator = placebo £33.29 0.01 £3,950 per PSA results show that at a
410 (a)
2010 applicable serious QALY gained threshold of £20,000, there is an
(b)
limitations Patient data taken from the 86% probability that glucosamine
GUIDE study .
185 is cost-effective compared with
Update 2014
placebo.
39
Black 2009 Partially Minor Comparator = standard care £2405 0.11 £21,335 per Deterministic sensitivity analysis
(c) (d)
applicable limitations QALY gained revealed that estimates were most
Baseline clinical characteristics affected by changed in QoL gain
were taken from an RCT in the associated with the therapy.
344 Probabilistic sensitivity analysis
Czech Republic , and inputs
from various other RCT’s. also revealed uncertainty around
Costs were from the UK (reported the magnitude of the QALY gain,
268
from a UK study ) and include and reported a probability of cost-
healthcare costs of OA patients. effectiveness at £20,000 of 43%.
(a) Healthcare perspective from Spain, with patients recruited from rheumatology centres. WOMAC scores were converted to HUI3.
(b) Time horizon is short (6 months); side effects not included; only drug costs are included; intervention costs are from market prices and are per day rather than unit costs.
(c) WOMAC scores were converted to HUI3.
(d) Side effects not included. A little unclear what the comparators are i.e. what constitutes standard care?
(e) Both of these studies use effects taken from studies using licensed glucosamine sulphate preparations.

192
Osteoarthritis
Table 118: Economic evidence profile: Chondroitin versus placebo

Incremental
Incremental effects Incremental
cost per (QALYs) per cost per QALY
(d)
Bruyere 2009 Partially Potentially Patient data taken from the £591 0.025 £23,637 per Consisted of calculating the ICER
52 (a) 229 (e)
applicable serious STOPP study (minimum QALY gained based on a minimum price of
(b) (c)
limitations CS cost) chondroitin, and again for the
maximum price.
Update 2014
£949
(maximum £37,962 per
(f)
CS cost) QALY gained
(a) European setting; uses VAS version of the WOMAC.

(b) Limited time horizon (24 months); side effects not captured; only costs of chondroitin are reported – not of rescue medication; no unit costs; doesn’t include a proper cost breakdown of
each intervention, and based on the cost of chondroitin which the authors state they are using – the incremental costs are underestimated; limited sensitivity analysis.
(c) The paper reported that the ICERs were calculated using minimum (£0.81) and maximum (£1.30) public costs of the branded chondroitin sulfate treatment in Europe. However, table 2 in
the paper, which reports the incremental cost effectiveness, has underestimated the costs by approximately half. Thus the incremental costs reported here are calculated based on the
chondroitin sulfate costs stated in the paper. (It is assumed that the placebo costs are zero as these are not mentioned in the paper).
(d) Not specifically mentioned – calculated
(e) Based on the minimum cost of chondroitin sulfate.
(f) Based on the maximum cost of chondroitin sulfate.

193
Osteoarthritis
The Black study conducted the most robust sensitivity analysis of the three published papers, and
found that the QoL gain is the main parameter causing variation in the results.
In the CG59 analysis, WOMAC scores were mapped onto EQ-5D using the model by Barton22 which
may be preferable to the mapping method used in Scholtissen 2010 410 and Black 2009 39 where
WOMAC scores were mapped onto HUI3.
The clinical studies included in the CG59 economic analysis are in line with the rest of the studies
included in this update, therefore the conclusions of the economic analysis are deemed still
applicable to the current evidence base.
At the time of writing of CG59, no licensed glucosamine sulfate product was available in the UK
(although it was available over the counter) – whereas now there is (the most recent cost from BNF is
£18.20 for 1 month supply).
The difference in the cost between the two identified glucosamine studies can partly be explained by
the difference in the acquisition costs. According to the Scholtissen paper, glucosamine is cheaper
than paracetamol (£0.19 and £0.26 (per day) respectively), whereas in the Black study, glucosamine
is costed at approximately £0.61 per day, which is very similar to the UK cost.
In the Bruyere study, the acquisition cost is £1.30 per day (this is the maximum cost – the cost-
effectiveness ratio is also calculated based on a minimum cost of chondroitin in Europe, which is
£0.81 per day).
Thus the higher drug acquisition costs of the Bruyere paper explain why it has the largest incremental
Update 2014
cost-effectiveness ratio of the three papers.
Clinical
All glucosamine preparations (hydrochloride and sulfate) vs placebo-knee OA

 Fourteen studies with 2218 people with knee osteoarthritis showed that there may be no
clinically important difference between all glucosamine preparations and placebo at decreasing
pain (pooled measures across different scales) [VERY LOW ].
 Eight studies with 671 people with knee osteoarthritis showed that there may be no clinically
important difference between all glucosamine and placebo at decreasing pain (pooled measures
across different scales) at a follow up of less than three months [VERY LOW ].
 Six studies with 1547 people with knee osteoarthritis showed that there may be no clinically
important difference between all glucosamine and placebo at decreasing pain (pooled measures
across different scales) at a follow up of greater than three months [VERY LOW].
 Ten studies with 1867 people with knee osteoarthritis showed that there may be no clinically
important difference between all glucosamine preparations and placebo at decreasing pain
measured on the WOMAC scale at both short and long term follow up [MODERATE].
 Ten studies with 1867 people with knee osteoarthritis showed that there may be no clinically
important difference between all glucosamine preparations and placebo at improving function
measured on the WOMAC scale at both short and long term follow up [MODERATE].
 Seven studies with 1240 people with knee osteoarthritis showed that there may be no clinically
important difference between all glucosamine preparations and placebo at decreasing stiffness
measured on the WOMAC scale at both short and long term follow up [LOW].
Osteoarthritis
 Three studies with 918 people with knee osteoarthritis showed that that there may be no
clinically important difference between all glucosamine preparations and placebo at improving
responder rate according to the OMERACT- OARSI criteria at both short term and long term follow
up. [VERY LOW].
 One study with 78 people with knee osteoarthritis showed that there may be no clinically
important difference between all glucosamine preparations and placebo at improving responder
rate according to the OMERACT- OARSI criteria at follow up less than three months [LOW ].
 Two studies with 840 people with knee osteoarthritis suggested that all glucosamine preparations
may be clinically more effective than placebo at improving responder rate according to the
OMERACT- OARSI criteria at follow up greater than three months, but there was some
uncertainty. [VERY LOW ].
 Thirteen studies with 1790 people with knee osteoarthritis showed that there may be no
difference between all glucosamine preparations and placebo with respect to adverse event
profile at both short and long term follow up [MODERATE].
All glucosamine preparations (hydrochloride and sulfate) vs placebo-hip OA
 One study with 222 people with hip osteoarthritis showed that there may be no clinically
measured on the WOMAC scale at both short and long term follow up [HIGH].
measured on the WOMAC scale at follow up greater than three months [HIGH].
Update 2014
important difference between all glucosamine preparations and placebo at improving function
important difference between all glucosamine preparations and placebo at decreasing stiffness
 One study with 222 people with knee osteoarthritis showed all glucosamine preparations and
placebo may be similar with respect to adverse event profiles at follow up greater than three
months [HIGH].
All glucosamine preparations (hydrochloride and sulfate) vs NSAIDs- knee OA
 Four studies with 997 people with knee osteoarthritis suggested that all glucosamine preparations
and NSAIDs may be similarly effective at decreasing pain (pooled measures across different
scales) at both short and long term follow up [VERY LOW ].
scales) at follow up less than three months [VERY LOW].
scales) at follow up greater than three months [VERY LOW].
and NSAIDs may be similarly effective at improving function measured with the Lequesne index at
both short and long term follow up [VERY LOW].
 One study with 189 people with knee osteoarthritis showed that all glucosamine preparations and
NSAIDs were similarly effective in improving function measured with Lequesne Index at follow up
of less than three months [HIGH].
Osteoarthritis
 One study with 156 people with knee osteoarthritis suggested that all glucosamine preparations
may be clinically more effective than NSAIDs at improving function measured with the Lequesne
index at follow up greater than three months, although there was uncertainty surrounding this
effect [MODERATE].
 One study with 635 people with knee osteoarthritis suggested that all glucosamine preparations
and NSAIDs may be similarly effective with respect to patient global assessment of disease status
at follow up greater than three months, [VERY LOW ].
 Four studies with 580 people with knee osteoarthritis showed that there are fewer patients
reporting adverse events (including GI, CV, pruritis and joint swelling) in the all glucosamine
preparations group compared to the placebo group at both short and long term follow up
[MODERATE].
 Three studies with 415 people with knee osteoarthritis showed that there are fewer patients
preparations group compared to the placebo group at follow up of less than three months
[MODERATE].
 One study with 165 people with knee osteoarthritis showed that there are fewer patients
preparations group compared to placebo group at follow up of greater than three months [HIGH].
Licensed glucosamine preparations(evidence only for glucosamine suphate) vs placebo-knee OA
 Five studies with 800 people with knee osteoarthritis suggested that licensed glucosamine
preparations may be clinically more effective than placebo at decreasing pain (pooled measures
across different scales) at both short and long term follow up, however there was uncertainty
Update 2014
surrounding this effect [VERY LOW].
 One conference abstract with 20 people with knee osteoarthritis suggested that licensed
glucosamine preparations may be clinically more effective than placebo at decreasing pain
(pooled measures across different scales) at both short term follow up, however there was
uncertainty surrounding this effect [VERY LOW].
 Four studies with 780 people with knee osteoarthritis suggested that that there may be no
clinically important difference between licensed glucosamine preparations and placebo at
decreasing pain (pooled measures across different scales) at long term follow up [VERY LOW].
 Three studies with 624 people with knee osteoarthritis showed that there may be no clinically
important difference between licensed glucosamine preparations and placebo at decreasing pain
measured on the WOMAC scale at follow up of more than three months [MODERATE].
 Three studies with 624 people with knee osteoarthritis showed that there may be no clinically
important difference between licensed glucosamine preparations and placebo at improving
function measured on the WOMAC scale at a follow up of greater than three months
[MODERATE].
 One study with 202 people with knee osteoarthritis showed that that there may be no clinically
important difference between licensed glucosamine preparations and placebo at decreasing
stiffness measured on the WOMAC scale at follow up greater than three months [MODERATE].
 Five studies with 951 people with knee osteoarthritis suggested that there may be no clinically
function measured with Lequesne index at both short and long term follow up [VERY LOW ].
 Two studies with 383 people with knee osteoarthritis suggested that there may be no clinically
function measured on the Lequesne index at a follow up of less than three months [MODERATE].
Osteoarthritis
 Three studies with 563 people with knee osteoarthritis suggested that licensed glucosamine
preparations may be clinically more effective than placebo in improving function measured on the
Lequesne index at a follow up of greater than three months, although there was uncertainty
 Two studies with 414 people with knee osteoarthritis suggested that licensed glucosamine
preparations may be clinically more effective at bringing about a change in minimum joint space
width loss at follow up greater than three months[LOW].
 One study with 212 people with knee osteoarthritis showed that licensed glucosamine
preparations and placebo were similarly effective in maintaining mean joint space width at follow
up greater than three months [MODERATE].
 One study with 210 people with knee osteoarthritis suggested that licensed glucosamine
preparations may be clinically more effective than placebo at improving responder rate according
to the OMERACT OARSI criteria at a follow up of greater than three months, however there was
uncertainty surrounding this effect [MODERATE].
 Seven studies with 1211 people with knee osteoarthritis showed that there may be no difference
between licensed glucosamine preparations and placebo in the adverse event profile at both
short and long term follow up [MODERATE y].
 Three studies with 431 people with knee osteoarthritis suggested that there may be fewer people
reporting adverse events in the licensed glucosamine preparations group compared to the
placebo group at a follow up of less than three months, although there was uncertainty
surrounding this effect. [VERY LOW].
 Four studies with 780 people with knee osteoarthritis showed that there may be no difference
Update 2014
between licensed glucosamine preparations and placebo in the adverse event profile at a follow
up of greater than three months [MODERATE].
Licensed glucosamine preparations (evidence only for glucosamine sulfate) vs NSAIDs-knee OA

preparations may be clinically more effective than NSAIDs at decreasing pain at follow up of
greater than three months; however there is uncertainty surrounding this effect [MODERATE].
preparations may be clinically more effective than NSAIDs at improving function measured with
the Lequesne index at follow up of greater than three months; however there is uncertainty
surrounding this effect [MODERATE].
 One study with 165 people with knee osteoarthritis showed that there were fewer people
reporting adverse events in the licensed glucosamine preparations group compared to the NSAID
group at a follow up of greater than three months [HIGH].
Licensed glucosamine preparations (evidence only for glucosamine sulfate) vs paracetamol-knee OA

preparations and paracetamol may be similarly effective in decreasing pain measured on the
WOMAC scale at follow greater than three months [MODERATE].
preparations and paracetamol were similarly effective in improving function measured on the
WOMAC scale at follow greater than three months [HIGH].
preparations and paracetamol were similarly effective in improving function measured wth the
Lequesne index at follow greater than three months [HIGH].
Osteoarthritis
Update 2014
preparations and paracetamolmay similarly effective in improving responder rate according to the
OMERACT-OARSI criteria at follow greater than three months [MODERATE].
Chondroitin sulfate vs placebo- knee OA
 Seventeen studies with 2335 people with osteoarthritis of the knee showed that chondroitin was
clinically more effective than placebo at decreasing pain measured on the visual analogue
scale(VAS) at both short term and long term follow up but there was some uncertainty. [VERY
LOW].
 Four studies with 365 people with osteoarthritis of the knee showed that chondroitin was
scale(VAS)at follow of less than 3 months [LOW].
 Thirteen studies with 1970 people with osteoarthritis of the knee showed that chondroitin may
be clinically more effective than placebo at decreasing pain measured on the visual analogue
scale(VAS) at follow of greater than 3 monthsbut there was some uncertainty. [VERY LOW].
 Four studies with 1622 people with osteoarthritis of the knee showed that there may be no
clinically important difference between chondroitin and placebo at decreasing pain measured on
the WOMAC scale at follow of greater than 3 months [MODERATE].
 One study with 631 people with osteoarthritis of the knee showed that there may be no clinically
important difference between chondroitin and placebo at improving function measured on the
WOMAC scale at follow of greater than 3 months [HIGH].
important difference between chondroitin and placebo at improving stiffness measured on the
Update 2014
WOMAC scale at follow of greater than 3 months [HIGH].
 Three studies with 948 people with osteoarthritis of the knee showed that chondroitin may be
clinically more effective in bringing about change in minimum joint space width loss at a follow up
of more than 13 weeks compared to placebo [MODERATE].
 Two studies with 938 people with osteoarthritis of the knee suggested that there may be no
clinically important difference between chondroitin and placebo at improving responder rate
according to OMERACT- OARSI criteria at follow up greater than 3 months [MODERATE].
 One study with 116 people with osteoarthritis of the knee suggested that there may be no
clinically important difference between chondroitin and placebo at improving quality of life
measured by physical component of SF36 scale at follow up less than 3 months [LOW ].
important difference between chondroitin and placebo at improving quality of life measured by
mental component of SF36 scale at follow up less than 3 months [MODERATE].
physical component of SF12 scale at follow up greater than 3 months [MODERATE].
 One study with 307people with osteoarthritis of the knee showed that there may be no clinically
mental component of SF12 scale at follow up greater than 3 months [MODERATE].
 Two studies with 938 people with osteoarthritis of the knee showed that there may be no
clinically important difference between chondroitin and placebo with respect to patient’s global
assessment of disease status at follow up greater than 3 [MODERATE].
 Tweleve studies with 2578 people with osteoarthritis of the knee showed that there may be no
difference between chondroitin and placebo int the total number of people reporting adverse
Osteoarthritis
events (GI, cardiovascular, infections, pruritis and back pain)at short term and long term follow up
[MODERATE].
 Two studies with 243 people with osteoarthritis of the knee suggested that there may be no
difference between chondroitin and placebo in the number of people reporting adverse events
events (GI, cardiovascular, infections, pruritis and back pain) at follow up less than 3 months
[VERY LOW].
 Ten studies with 2335 people with osteoarthritis of the knee suggeseted that there may be no
events (GI, cardiovascular, infections, pruritis and back pain) at follow up greater than 3 months
[Low quality].
Chondroitin sulfate vs. placebo- hip OA
 One study with 104 people with osteoarthritis of the hip suggested that chondroitin may be
scale(VAS)at follow up greater than 3 months, however there was some uncertainty surrounding
this effect [LOW].
Chondroitin sulfate vs. placebo- hand OA
 One study with 139 people with osteoarthritis of the hand showed that there may be no clinically
important difference between chondroitin and placebo at decreasing pain measured on the visual
analogue scale (VAS)at follow up of greater than 3 months [HIGH].
 One study with 139 people with osteoarthritis of the hand showed that there may be no clinically
important difference between that chondroitin and placebo at improving function measured by
the FIHOA score at follow up greater than 3 months [HIGH].
Update 2014
• One study with 162 people with osteoarthritis of the hand showed that three may be no
(GI, musculoskeletal, disorders relating to the nervous system, skin and subcutaneous tissue) at
follow up of greater than 3 months [HIGH].
Chondroitin sulfate vs NSAIDs-knee OA
 One study with 636 people with osteoarthritis of the knee showed that chondrotin and NSAIDs
may be similarly effective at decreasing pain measured on the WOMAC scale at follow up of
greater than 3 months [HIGH].
may be similarly effective at improving function measured on the WOMAC scale at follow up of
may be similarly effective at decreasing stiffness measured on the WOMAC scale at follow up of
may be similarly effective at improving responder rate according to the OMERACT-OARSI criteria
at follow up of greater than 3 months [HIGH].
may be similarly effective with respect to patient’s global assessment of disease status at follow
up of greater than 3 months [HIGH].
 One study with 636 people with osteoarthritis of the knee suggested that there may be fewer
people withdrawing due to adverse events adverse events in the NSAID group compared to the
chondroitin group at follow up of greater than 3 months, however there was some uncertainty
surrounding this effect [MODERATE].
Glucosamine sulfate or glucosamine hydrochloride and chondroitin sulfate vs. placebo- knee OA
Osteoarthritis
 Two studies with 719 people with knee osteoarthritis showed that there may be no clinically
important difference between a combination of glucosamine and chondroitin and placebo in
decreasing pain measured on the WOMAC scale at a follow up greater than three months [LOW].
 Two studies with 719 people with knee osteoarthritis showed that there may be no clinically
improving function measured on the WOMAC scale at follow up of greater than three months
[LOW].
decreasing stiffness measured on the WOMAC scale at follow up greater than three months
[LOW].
important difference between a combination of glucosamine and chondroitin and placebo with
respect to patient’s global assessment of disease status at follow up greater than three months
[LOW].
 One study with 630 people with knee osteoarthritis suggested that there may be no clinically
improving responder rate according to the OMERACT-OARSI criteria at follow up greater than
three months [VERY LOW].
 One study with 93 people with knee osteoarthritis suggested that there may be no clinically
important difference between a combination of glucosamine and and placebo in improving
function measured with the Lequesne index at follow up greater than three months, but the
effect size was too small to be clinically effective and there was some uncertainty [LOW].
Update 2014
 One study with 59 people with knee osteoarthritis suggested that a combination of glucosamine
and chondroitin may be clinically more effective than placebo at decreasing pain measured on the
visual analogue scale (VAS) at follow up less than three months, however there was uncertainty
surrounding this effect. [MODERATE].
 One study with 59 people with knee osteoarthritis suggested that a combination of glucosamine
and chondroitin may be clinically more effective than placebo at improving quality of life
measured by the physical component of SF36 at follow up of less than three months, however
there was uncertainty surrounding this effect [LOW].
 One study with 59 people with knee osteoarthritis suggested that placebo may be clinically more
effective than a combination of glucosamine and chondroitin at improving quality of life
measured by the mental component of SF36 at follow up of less than three months [MODERATE].
Glucosamine sulfate or glucosamine hydrochloride and chondroitin sulfate vs. NSAIDs- knee OA
 One study with 635 people with knee osteoarthritis showed that a combination of glucosamine
and chondroitin and NSAIDs were similarly effective at decreasing pain measured on the WOMAC
scale at follow up of greater than three months [LOW].
and chondroitin and NSAIDs were similarly effectiveat improving function measured on the
WOMAC scale at follow up of greater than three months [LOW].
and chondroitin and NSAIDs were similarly effective at decreasing stiffness measured on the
WOMAC scale at follow up of greater than three months [LOW].
and chondroitin and NSAIDs were similarly effective at improving patient’s global assessment of
disease status at follow up of greater than three months [LOW].
Osteoarthritis
and chondroitin and NSAIDs were similarly effective at improving responder rate according to
OMERACT-OARSI criteria at follow up of greater than three months [LOW].
Economic
 One study found that glucosamine sulfate was not cost effective compared with current care
(ICER = £21,335). This study was partially applicable with minor limitations.
 One study found that glucosamine sulfate was dominant compared with paracetamol, and cost
effective compared with placebo (ICER = £3,950). This study was partially applicable with
potentially serious limitations.
 One study found Chondroitin sulfate was not cost effective compared with placebo (ICER =
£23,637). This study was partially applicable with potentially serious limitations.

Recommendation
16.Do not offer glucosamine or chondroitin products for the management
of osteoarthritis. [2014]
Relative values of
The GDG considered that pain, function, structure modification and adverse
different
events profile to be the critical outcomes for decision-making. Other
outcomes
important outcomes were stiffness, the OMERACT OARSI responder criteria
and the patient’s global assessment.
Update 2014
Trade off between
The GDG reviewed the evidence for the use of glucosamine and chondroitin
clinical benefits
in isolation and in combination. The evidence for their use was also
and harms
considered in relation to the joint involved. The GDG identified the important
joints as hip; knee and hand.
The effect of the nutraceuticals can be divided into symptom modifying

effects, and structure modifying effects. After reviewing the clinical evidence,
the GDG felt that the symptom modifying data (e.g. improvement in pain or
function) were not positive enough to warrant a change in the
recommendation. The GDG noted that any degree of structure modification
should be taken as clinically important, thus the MID chosen for structural
modification outcomes was the line of no effect or zero.The relative lack of
data,inconsistent effects on structural modification, and radiological method
of measurement of structure modification were also noted.
Glucosamine
The GDG considered that there was a no clinically important difference with
all glucosamine preparations when compared to placebo in OA of the knee
for the critical outcomes of pain, (both for pooled measures of pain and
WOMAC) WOMAC function and WOMAC stiffness at both short and long
term, and the OMERACT OARSI responder criteria at less than three months.
The level of evidence ranged from moderate to very low quality.
The GDG considered that despite the evidence for a clinically significant
reduction of pooled pain with licensed glucosamine sulfate at less than 3
months, the evidence stemmed from only one study 365 with 20 participants
Osteoarthritis
and thus was deemed insufficient as a basis for a recommendation on the

analgesic effect of licensed glucosamine sulfate.
There was no clinically important difference between glucosamine and

placebo in osteoarthritis of the hip in pain, WOMAC pain, WOMAC stiffness
or WOMAC function at more than three months.
There was no clinically important difference with licensed glucosamine

sulfate when compared with placebo in OA of the knee for pain (pooled
measures) for long-term outcomes. There was a possible clinical benefit of
licenced glucosamine when compared to placebo in OA of the knee for the
Lequesne index at more than three months, and the OMERACT-OARSI
responder index at more than three months but there was uncertainty in
these effects and the evidence ranged from very low to moderate quality.
The effect size of licensed glucosamine sulfate was too small to be clinically
effective for WOMAC pain, function, and stiffness at more than three months
and the evidence was of moderate quality. This was also the case for
minimum joint space width, where despite a clinical effect, the evidence
ranged from very low to moderate quality.
There was a possible clinical benefit with licensed glucosamine sulfate when
compared to NSAIDs for pain in OA of the knee (pooled measures in the long
term) but there was uncertainty in the effect and the evidence was of
moderate quality.
Update 2014
Low quality evidence suggested that licensed glucosamine sulfate may be
more effective at bringing about a change in minimum joint space width loss
at follow up of greater than three months compared to placebo, but
moderate quality evidence from one three year study suggested licensed
glucosamine sulfate and placebo were similarly effective in maintaining
mean joint space width at follow up greater than three months.
Overall, the GDG considered that there was no difference in safety between
licensed glucosamine sulfate and placebo.
One study (Herrero-Beaumont 2007) examined the use of licenced

glucosamine sulfate compared to paracetamol in knee osteoarthritis and
found no clinically important difference in the reduction of pain as measured
by the WOMAC scale, improvement in function as measured on the WOMAC
scale and the Lequesne index, or the numbers of responders according to
OMERACT-OARSI criteria at 6 months. The evidence ranged from moderate
to high quality.
One conference abstract (Patru 2012) examined the use of licenced

glucosamine sulfate compared to paracetamol in hand osteoarthritis. Little
methodological information was available from the abstract and its evidence
was deemed of low quality. In the critical outcome of pain, there was similar
efficacy of both agents.
Glucosamine and chondroitin in combination
There was a possible clinical benefit with glucosamine and chondroitin in

combination when compared to placebo in osteoarthritis of the knee in
decreasing pain as measured by a VAS, and improving the SF-36 physical
Osteoarthritis
component at less than 3 months, but no clinically important difference

between the two in terms of WOMAC pain, function and stiffness at more
than 3 months was shown. As such, the GDG considered that the evidence
for an analgesic effect with the use of glucosamine and chondroitin in
combination was neglible.
Chondroitin
The GDG discussed the clinical evidence for chondroitin which showed a
possible benefit of chrondroitin over placebo at reducing pain as measured
on a visual analogue scale (VAS) at combined short and long term outcomes
although there was uncertainty surrounding these effects and the quality of
the evidence ranged from low to very low. At short term outcomes alone
(<13 weeks) chondroitin is favoured compared to placebo, however the
quality of this evidence was low.
Moderate quality evidence suggested chondroitin may be more effective in

bringing about change in minimum joint space width loss at a follow up of
more than 13 weeks compared to placebo.
Economic Analysis from the previous guideline looked at the cost-effectiveness of

considerations glucosamine or chondroitin compared to placebo. This found that only
glucosamine sulfate was cost effective with a cost per QALY below £20,000.
However the CG59 analysis was deemed to be simplistic and was assessed as
having potentially serious limitations. These include only considering the
direct cost of the interventions, not considering adverse events or decrease
in use of other medicines due to increased wellbeing .
Three cost-effectiveness analyses were identified from the update search for
this area. One study by Bruyere (2009) found that chondroitin sulfate was
not cost effective compared with placebo. This study had potentially serious
limitations as it underestimated the total costs. For this reason, the costs and
ICER were recalculated by the NCGC health economist using the data
reported in the study and more recent UK costs. The GDG were satisfied by
this evidence that chondroitin was not cost effective.
Two studies looked at the cost-effectiveness of glucosamine. A study by Black

(2009) found glucosamine sulfate was not cost effective compared to usual
care. The other study by Scholtissen (2010) found that glucosamine sulfate
was cost effective compared to paracetamol and placebo. The GDG placed a
higher weighting on the glucosamine study by Black, as this was of higher
quality, was a Health Technology Appraisal and was more applicable to the
NHS setting (UK study).
The difference in the cost per QALY between the two glucosamine studies
appeared substantial, the main contributor to this difference are the drug
costs from each study. The drug costs in the Scholtissen (2010) study appear
very low compared to the other studies and to the actual drug cost in the UK,
which would bias the results by making glucosamine more cost effective.
Additionally, glucosamine being cheaper than paracetamol in this study does
not reflect actual UK drug costs.
Update 2014
The possible concern of omitting side effects was discussed, as none of the
three studies incorporated the side effects of the drugs. If adverse events
Osteoarthritis
were included in the Scholtissen study, then glucosamine may appear even
more cost effective compared to paracetamol. It is accepted that
nutraceuticals are relatively safe, however it was noted that if the Black
paper (where the cost per QALY is just over the threshold of £20,000)
included side effects of both intervention and comparator, then the side
effects associated with current care (which includes medications) could
cause glucosamine to appear more favourable. Additionally, if nutraceuticals
reduce the need for other drugs in the future, then excluding this will also
bias against glucosamine. Therefore glucosamine might be more cost
effective if these factors were taken into account.
Although glucosamine may appear cost effective in some studies (Scholtissen

and CG59 analysis) or when side effects are taken into account in the Black
study, by looking at the results of the clinical review the GDG considered the
increase in effectiveness observed with glucosamine was not clinically
important and therefore considered the results of the cost-effectiveness
analyses driven by negligible and non-significant improvement. Interventions
should first be proven effective (compared to placebo) before considering
cost effectiveness.
The GDG noted the lack of clinical data on structural modification. The
decision model in the study by Black (2009) included a health state entitled
‘progression to total knee replacement’. There was a lower probability of
progressing to this state for those patients in the glucosamine group (these
probabilities were taken from Bruyere (2008), which found a clinically
significant decrease and delayed cumulative incidence of total knee
replacement for people who had previously taken glucosamine sulfate). As
Bruyere (2008) was the only study identified which looked at the outcome of
time to joint replacement, the GDG were uncertain about its effects. If this
were not included in the Black model, it is likely that the ICER would have
been higher. If it is indeed the case that glucosamine reduces the need for
joint replacement, then this will have a positive impact on downstream
resource use and costs.
Data in the meta-analysis conducted by the GDG was stratified by joint type
Quality of
and by licensing indication. All relevant studies assessing licensed
evidence
glucosamine sulfate were reviewed and stratified accordingly either based on
the information provided in the study or as indicated by the Cochrane
Review. The GDG are aware of licensed preparations of glucosamine
hydrochloride, but none of the retrieved studies has referred to a licensed
preparation. No separate analysis of studies with unlicensed preparations of
glucosamine sulfate was undertaken as it was recognised that such studies
may have potentially involved the use of preparations licensed outside of the
UK.
All studies included in the clinical evidence review included unlicensed

preparations of chondroitin.
The GDG considered the quality of evidence when considering whether any
changes to the existing recommendation should be made. All glucosamine
Update 2014
preparations when compared to placebo in OA of the knee for the critical

outcome of pain showed no clinically important difference in the effect and
the evidence ranged from very low to low quality.
Osteoarthritis
After examining a sensitivity analysis in the clinical review, which separated

high and low quality studies (i.e. low and high risk of bias respectively), the
GDG decided that the overall evidence on effectiveness of glucosamine
sulfate and chondroitin remained very limited and uncertain.
Other The GDG noted that the evidence demonstrated that there was no clinically
considerations important difference between chondroitin and placebo in WOMAC pain,
stiffness or function at time points greater than 3 months even though low
quality short term outcome data demonstrated efficacy compared to placebo
at <13 weeks . The GDG felt overall therefore that this did not demonstrate
clinical efficacy and chose not to recommend chondroitin products.
The GDG also considered that despite the evidence for a clinically significant
reduction of pain with licensed glucosamine sulfate in the short term,
thisevidence stemmed from only one study with 20 patients365 and as such
this was deemed insufficient evidence for a positive recommendation.
The GDG also noted the lack of data on structural modification. There was
limited evidence identified for the time to joint replacement outcome. The
GDG noted a study (Bruyere et al, 2008) which followed up patients from two
RCTs, and the results showed fewer joint replacement operations in the
group who took glucosamine sulfate in the RCTs.
The GDG were aware that many combinations and compounds of
Update 2014
nutraceuticals are available for purchase as health food supplements and are
sold over the counter in a variety of settings. The GDG were concerned that
the advice contained within a NICE guideline may influence people with
osteoarthritis in their purchasing patterns of these products. The GDG felt
that the over the counter preparations were not always regulated in terms of
their strength and purity and felt strongly that they should make comment
only on products whose content is licensed and regulated as outlined in the
BNF and on the advice of the Medicines and Healthcare Regulatory Authority
(MHRA). The technical team therefore sought advice from the GDG,
including the GDG pharmacist,on the available licensed nutraceuticals in the
UK and have considered this evidence when discussing advice for the NHS.
The GDG have assumed that Glusartel is the licensed UK equivalent of the
Rottapharm preparation, which is mentioned in the Cochrane Review and
throughout the studies included in this evidence review.
Therefore, in light of the overall limited and uncertain evidence on

effectiveness of all glucosamine and chondroitin preperations, the GDG
chose not to recommend them for use in the NHS.
Research recommendation
The GDG agreed to draft a research recommendation on therapies that can

modify joint structures resulting in delayed structural progression and
improved patient outcomes. For further details on research
recommendations, see Appendix N.
Osteoarthritis
Update 2014
8.5 Acupuncture
8.5.1 Introduction
The Chinese discovered acupuncture about 2000 years ago, and their explanation of how it works has
changed over time, as world views evolved. In the 1950s, all these explanations were combined into
the system currently known as ‘traditional Chinese acupuncture’. This approach uses concepts that
cannot be explained by conventional physiology, but remains the most common form of acupuncture
practised throughout the world. In the UK, doctors and physiotherapists are increasingly using
acupuncture on the basis of neurophysiological mechanisms, known as ‘Western medical
acupuncture’, whereas acupuncturists outside the NHS tend to use traditional Chinese acupuncture,
and sometimes add Chinese herbs.
Acupuncture involves treatment with needles, and is most commonly used for pain relief. They will
be either manipulated to produce a particular ‘needle sensation’, or stimulated electrically
(electroacupuncture) for up to 20 minutes. Some practitioners also use moxa, a dried herb which is
burned near the point to provide heat. A course of treatment usually consists of six or more sessions
during which time, if a response occurs, pain relief gradually accumulates.
The potential mechanisms of action of acupuncture are complex in terms of neurophysiology, and
involve various effects including the release of endogenous opioids.
Research into acupuncture has also proved complex. As with surgery and physiotherapy, it is
impossible to blind the practitioner and it is difficult to blind the participant. The GDG wished to
review the evidence regarding the use of acupuncture in the management of osteoarthritis.
Update 2014
8.5.2 What is the clinical and cost-effectiveness of acupuncture versus sham treatment ( sham
control) and other interventions in the management of osteoarthritis?
For full details see review protocol in Appendix C. Outcomes for this review were grouped and
evaluated at two time points:
o Short term- Time points less than 3 months and closest to 8 weeks after baseline
o Long term- Time points greater than or equal to 26 weeks after baseline
Trials which assessed outcomes at less than 6 weeks follow-up were excluded from this review as less
than this length of follow-up was not considered adequate to assess the effectiveness of acupuncture
for OA.

We searched for randomised trials comparing the effectiveness of acupuncture versus sham ( sham
control) treatment or other interventions for the management of OA.
One Cochrane review278 on the use of acupuncture for the management of peripheral joint arthritis
was identified and was updated as part of this review The Cochrane review included 16 RCTs. Of
these, 10 RCTs compared acupuncture to sham acupuncture. Nine of these RCTs were in people with
OA of the knee and one was in people with OA of the hip.. In addition, six additional RCTs were
identified since the publication of the Cochrane review215, 216, 226, 253, 261, 432.
Of the six additional studies identified since publication of the Cochrane review four were found to
compare acupuncture to sham acupuncture 215,226,261,432. Of the other two studies one 215 compared
acupuncture to transcutaneous electrical nerve stimulation (TENS) and the other 253 compared
acupuncture to usual care (which included any appointments, medications and interventions sought
by participants from any health practitioner). All the studies evaluated acupuncture based on
Osteoarthritis
traditional Chinese acupuncture points. Of these, one reported Knee Society Scores for pain and
function and the results are presented separately261. Another RCT presented the results in graphs
and did not report standard deviations or standard errors for any of the values215. The data for this
RCT have not been included in the meta- analysis, although the information is presented in the
evidence tables.
In addition to the Cochrane review and updated studies, an Individual Patient Data Meta-Analysis 474
was also identified. This IPD involved analysis of acupuncture vs. sham acupuncture and acupuncture
versus no acupuncture on people with OA. This study included only high quality studies with
Update 2014
adequate allocation concealment and studies that reported results at more than four weeks follow
up. Both fixed effects and random effects coefficients were calculated. For the comparison of
acupuncture versus sham acupuncture the effect sizes quoted from each constituent trial were
imputed into our meta-analysis at the appropriate time point for each trial, as the effect sizes quoted
in the IPD are likely to represent a more accurate estimate than those quoted in the original trials
due to the nature of the IPD analysis.
We set out to conduct sensitivity analysis for studies where blinding was adequate, as undertaken by
the Cochrane review. Among the studies comparing acupuncture to sham acupuncture, some trials
additionally reported the assessment of blinding by the participants150,226,404,432,498. When
acupuncture and sham were found to be indistinguishable, the sham was confirmed to have
achieved blinding. A sensitivity analysis was carried out with these trials in the meta-analyses. The
results of the sensitivity analysis are presented in a separate table (see Table 121).
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Table 119: Clinical evidence profile: Acupuncture versus sham acupuncture- Knee OA

Quality Importance
No of Other Acupunctu sham acupuncture Relative
studies considerations re for knee OA (95% CI)
Pain (change + final scores) WOMAC short term Better indicated by lower values): Berman 2004; Foster 2007; Jubb 2008; Sangdee 2002; Sangadee 2002* Scharf 2006; Suarez-Almazor
2010; Takeda 1994 ; Vas 2004; Witt 2005
a b
10 randomised serious serious no serious no serious none 1085 1205 - SMD 0.34 lower LOW CRITICAL
trials indirectness imprecision (0.57 to 0.11 lower)
Pain (change + final scores) VAS short term (Better indicated by lower values): Jubb 2008; Sangdee 2002; Sangadee 2002*; Suarez-Almazor 2010; Vas 2004
a b c
5 randomised serious very serious no serious serious none 323 477 - SMD 0.58 lower VERY LOW CRITICAL
trials indirectness (1.06 to 0.11 lower)
Pain short term- Knee society score (Better indicated by lower values): Lev-Ari 2011
Update 2014
a c
1 randomised serious no serious no serious serious none 28 27 - SMD 0.06 lower LOW CRITICAL
trials inconsistency indirectness (0.59 lower to 0.47
higher)
Function (change + final scores) WOMAC short term (Better indicated by lower values): Berman 2004; Foster 2007; Jubb 2008; Sangdee 2002; Sangadee 2002* Scharf 2006; Suarez-
Almazor 2010; Takeda 1994 ; Vas 2004; Witt 2005
a b
10 randomised serious serious no serious no serious none 1085 1200 - SMD 0.27 lower LOW CRITICAL
trials indirectness imprecision (0.42 to 0.11 lower)
Function- short term- Knee society score (Better indicated by lower values) Lev-Ari 2011
a c
1 randomised serious no serious no serious serious none 28 27 - SMD 0.28 higher LOW CRITICAL
higher)
Stiffness- WOMAC- short term- change + final scores (Better indicated by lower values): Jubb 2008, Sangadee 2002; Sangadee 2002*; Tsakeda 1994; Vas 2004; Witt 2005
a b c
6 randomised serious serious no serious serious none 335 268 - SMD 0.42 lower VERY LOW CRITICAL
trials indirectness (0.59 to 0.25 lower)
EuroQoL- short term (Better indicated by higher values): Jubb 2008
a c
1 randomised serious no serious no serious serious none 34 34 - SMD 0.43 higher LOW IMPORTANT
higher)

208
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SF12-Physical component- short term (Better indicated by higher values): Suarez-Almazor 2010
1 randomised no serious no serious no serious no serious none 153 302 - SMD 0.15 higher HIGH IMPORTANT
trials risk of bias inconsistency indirectness imprecision (0.04 lower to 0.35
higher)
SF12-Mental component - short term (Better indicated by higher values): Suarez-Almazor 2010
1 randomised no serious no serious no serious no serious none 153 302 - SMD 0.07 lower HIGH IMPORTANT
higher)
SF36 Physical component (change + final scores) short term (Better indicated by higher values): Berman 2004; Witt 2005
a
2 randomised serious no serious no serious no serious none 314 242 - SMD 0.22 higher MODERAT IMPORTANT
trials inconsistency indirectness imprecision (0.05 to 0.39 higher) E
SF36- Mental component- short term (Better indicated by higher values): Witt 2005
higher)
Update 2014
Pain- long term(Better indicated by lower values): Berman 2004; Foster 2007; Scharf 2006; Witt 2005
higher)
Function- long term (Better indicated by lower values): Berman 2004; Foster 2007; Scharf 2006; Witt 2005
trials risk of bias inconsistency indirectness imprecision (0.29 to 0.02 lower)
Stiffness – long term (Better indicated by lower values): Scharf 2006; Witt 2005
trials risk of bias inconsistency indirectness imprecision (0.27 lower to 0.00)
SF12- Physical component – long term-change scores (Better indicated by higher values): Scharf 2006
higher)
SF12- Mental component (change scores) – long term (Better indicated by higher values): Scharf 2006
higher)

209
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SF36 Physical component (change + final scores) long term (Better indicated by higher values): Berman 2004; Witt 2005
a
2 randomised serious no serious no serious no serious none 288 213 - SMD 0.17 higher MODERAT IMPORTANT
trials inconsistency indirectness imprecision (0.01 lower to 0.35 E
higher)
SF36- Mental component- long term (Better indicated by higher values): Witt 2005
higher)
OMERACT-OARSI response- long term: Berman 2004
a 3
1 randomised serious no serious no serious serious none 98/186 86/183 RR 1.12 56 more per 1000 LOW IMPORTANT
trials inconsistency indirectness (52.7%) (47%) (0.91 to (from 42 fewer to
1.38) 179 more)
Update 2014
effects analysis. A sensitivity analysis was conducted on the trials judged to have adequate blinding.
Table 120: Acupuncture versus sham acupuncture- Hip OA

Importan
Quality
sham ce
Design Risk of bias Inconsistency Indirectness Imprecision Acupuncture acupuncture for Absolute
hip OA
Pain VAS short term (Better indicated by lower values): Fink 2001
a b
1 randomised serious no serious no serious serious none 32 30 - SMD 0.2 lower (0.7 CRITICAL
trials inconsistency indirectness lower to 0.3 higher) LOW
Function- Lequesne(hip function index)-short term (Better indicated by lower values): Fink 2001

210
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a b
1 randomised serious no serious no serious serious none 32 30 - SMD 0.18 lower (0.68 CRITICAL
b) Outcomes were downgraded by one increment if the upper or lower 95% CI crossed the lower MID or the upper or lower 95% CI crossed the upper MID. Outcomes were downgraded by
two increments if the upper CI simultaneously crossed the upper MID and the lower CI crossed the lower MID.
Table 121: Acupuncture versus sham- Sensitivity analysis with trials judged to have adequate blinding1 -Knee OA
All trials Sensitivity analysis with blinded trials
No. of No. of
Update 2014
Outcome studies Effect size (95%CI) studies Effect size (95%CI)
32,150,226,4 150,226,404
Pain WOMAC- short term(Better indicated by lower 10 SMD 0.34 lower (0.57 lower to 0.11 5 SMD 0.15 lower [0.32 lower to 0.02
00,404,432,439, ,432,498
values) lower) higher]
471,498
226,400,432,4 226,432
Pain VAS- short term(Better indicated by lower 5 SMD 0.58 lower (1.06 to 0.11 lower) 2 SMD 0.22 lower [0.52 lower to 0.08
71
values) higher]
32,150,226,4 150,226,404
Function WOMAC- short term(Better indicated by 10 SMD 0.27 lower (0.42 to 0.11 lower) 5 SMD 0.16 lower [0.30 to 0.02 lower]
00,404,432,439, ,432,498
lower values)
471,498
226,400,439,4 226,498
Stiffness WOMAC- short term(Better indicated by 6 SMD 0.42 lower (0.59 to 0.25 lower) 2 SMD 0.37 lower [0.61 to 0.12 lower]
71,498
lower values)
32,498 498
SF36 Physical component- short term(Better 2 SMD 0.22 higher (0.05 to 0.39 higher) 1 SMD 0.44 higher [0.15 to 0.72 higher]
indicated by higher values)
1 Blinding was assessed to be successful in the following manner: At the end of a study, patients were given a questionnaire asking them what treatment they thought they had received during
the study. If there were no significant differences between the percentage of participants who answered for either intervention (acupuncture or sham), blinding was judged to have been
adequate. Trials where blinding was judged to be adequate are: Scharf 2006, Witt 2005, Foster2007, Jubb2008, Suarez-Almazor2010

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Table 122: Acupuncture vs. waiting list control or other active treatments- Knee OA
Quality assessment No of patients Effect (95%CI)
waiting list or other Importanc

Quality
No of Other Acupunctur active treatment controls Relative e
studies considerations e for knee OA post- (95% CI)
treatment scores analysis
Pain (final scores) Short Term- Acupuncture vs. waiting list control (Better indicated by lower values): Berman 1999; Itoh 2008; Lansdown 2009, Suarez-Almazor 2010, Tukmachi 2004;
Witt 2005, Witt 2006
7 randomised very no serious no serious no serious none 532 361 - SMD 0.89 lower CRITICAL
a
trials serious inconsistency indirectness imprecision (1.1 to 0.67 LOW
lower)
Pain ( final scores) Short Term- Acupuncture vs. supervised osteoarthritis education (Better indicated by lower values): Berman 2004
a c
1 randomised serious no serious no serious serious none 169 125 - SMD 0.51 lower CRITICAL
lower)
Update 2014
Pain (final scores) Short Term- Acupuncture as an adjunct to exercise based physiotherapy program (including supervised plus home exercises) vs exercise based physiotherapy program
alone (no adjuvant acupuncture) (Better indicated by lower values): Foster 2007
a
1 randomised serious no serious no serious no serious none 113 105 - SMD 0.12 lower CRITICAL
trials inconsistency indirectness imprecision (0.38 lower to MODERAT
0.15 higher) E
Pain (final scores) Short Term- Acupuncture vs. home exercises/advice leaflet alone (Better indicated by lower values): Williamson 2007
a c
trials inconsistency indirectness (0.54 lower to LOW
0.18 higher)
Pain (final scores) Short Term - Acupuncture vs. supervised exercise alone (Better indicated by lower values): Williamson 2007
a
0.23 higher) E
Pain (final scores) Short Term- Acupuncture vs. physician consultations (with a physiotherapy co-intervention) (Better indicated by lower values): Scharf 2006
a c
lower)
Pain (final scores) Short Term- Acupuncture vs. TENS (Better indicated by lower values): Itoh 2008
a
trials serious inconsistency indirectness imprecision (1.08 lower to LOW
0.88 higher)
Pain ( final scores) Short Term- Acupuncture vs. acupuncture + TENS (Better indicated by lower values): Itoh 2008

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c
1 randomised very no serious no serious very serious none 8 8 - SMD 0.32 higher CRITICAL
a
trials serious inconsistency indirectness (0.66 lower to VERY LOW
1.31 higher)
Pain (final scores) Short Term- Acupuncture + TENS vs. waiting list control (Better indicated by lower values): Itoh 2008
c
1 randomised very no serious no serious serious none 8 8 - SMD 0.68 lower CRITICAL
a
0.34 higher)
Pain (final scores) Short Term - Acupuncture + TENS vs TENS alone (Better indicated by lower values): Itoh 2008
c
1 randomised very no serious no serious very serious none 8 8 - SMD 0.4 lower CRITICAL
a
0.59 higher)
VAS pain (final scores) Short Term - Acupuncture vs. waiting list control (Better indicated by lower values):Itoh 2008; Suarez-Almazor 2010; Tukmachi 2004
b c
3 randomised very very serious no serious serious none 171 90 - SMD 0.5 lower CRITICAL
a
trials serious indirectness (0.76 to 0.24 VERY LOW
lower)
VAS pain (final scores) Short Term) - Acupuncture vs. home exercises/advice leaflet alone (Better indicated by lower values): Williamson 2007
a c
Update 2014
0.13 higher)
VAS pain (final scores) Short Term - Acupuncture vs. supervised exercise alone (Better indicated by lower values): Williamson 2007
a c
0.16 higher)
VAS pain (final scores) Short Term - Acupuncture vs. TENS (Better indicated by lower values): Itoh 2008
c
a
0.41 higher)
VAS pain (final scores) Short Term) - Acupuncture vs. acupuncture + TENS (Better indicated by lower values): Itoh 2008
c
1 randomised very no serious no serious very serious none 8 8 - SMD 0.08 higher CRITICAL
a
1.06 higher)
VAS pain (final scores) Short Term - Acupuncture + TENS vs. waiting list control (Better indicated by lower values): Itoh 2008
c
a
0.62 higher)
VAS pain (final scores) Short Term - Acupuncture + TENS vs. TENS alone (Better indicated by lower values): Itoh 2008
c
a

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0.29 higher)
Function (final scores) Short Term - Acupuncture vs. waiting list control (Better indicated by lower values): Berman 1999; Lansdown 2009; Suarez-Almazor 2010; Witt 2005; Witt 2006
a b
5 randomised serious serious no serious no serious none 510 342 - SMD 0.91 lower CRITICAL
trials indirectness imprecision (1.22 to 0.61 LOW
lower)
Function (final scores) Short Term - Acupuncture vs. supervised osteoarthritis education (Better indicated by lower values); Berman 2004
a c
lower)
Function (final scores) Short Term - Acupuncture as an adjunct to exercise based physiotherapy program (including supervised plus home exercises) vs exercise based physiotherapy
program alone (no adjuvant acupuncture) (Better indicated by lower values): Foster 2007
a
1 randomised serious no serious no serious no serious none 113 105 - SMD 0 higher CRITICAL
0.27 higher) E
Function (final scores) Short Term - Acupuncture vs. home exercises/advice leaflet alone (Better indicated by lower values): Williamson 2007
a c
Update 2014
0.15 higher)
Function (final scores) Short Term) - Acupuncture vs. supervised exercise alone (Better indicated by lower values): Williamson 2007
a
0.31 higher) E
Function (final scores) Short Term - Acupuncture vs. physician consultations (with a physiotherapy co-intervention) (Better indicated by lower values): Scharf 2006
a
1 randomised serious no serious no serious no serious none 314 309 - SMD 0.67 lower MODERAT CRITICAL
trials inconsistency indirectness imprecision (0.83 to 0.5 E
lower)
Stiffness (final scores) Short Term - Acupuncture vs. waiting list control (Better indicated by lower values): Lansdown 2009, Tukmachi 2004, Witt 2005, Witt 2006
b
4 randomised very serious no serious no serious none 335 244 - SMD 0.89 lower CRITICAL
a
trials serious indirectness imprecision (1.06 to 0.71 VERY LOW
lower)
Lequesne Index (final scores) Short Term) - Acupuncture vs. waiting list control (Better indicated by lower values): Berman 1999
1 randomised no serious no serious no serious no serious none 36 37 - SMD 0.98 lower HIGH CRITICAL
trials risk of bias inconsistency indirectness imprecision (1.47 to 0.49
lower)
EQ5D (final scores) Short Term) - Acupuncture vs. waiting list control (Better indicated by higher values): Lansdown 2009
c
1 randomised very no serious no serious very serious none 15 15 - SMD 0.19 higher IMPORTAN
a
trials serious inconsistency indirectness (0.53 lower to VERY LOW T

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0.91 higher)
SF12- Physical component (final scores) Short Term - Acupuncture vs. waiting list control (Better indicated by higher values): Suarez-Almazor 2010
c
1 randomised no serious no serious no serious serious none 153 302 - SMD 0.4 higher IMPORTAN
trials risk of bias inconsistency indirectness (0.21 to 0.6 MODERAT T
higher) E
SF12- Mental component (final scores) Short Term - Acupuncture vs. waiting list control (Better indicated by higher values): Suarez-Almazor 2010
1 randomised no serious no serious no serious no serious none 153 302 - SMD 0.27 higher IMPORTAN
trials risk of bias inconsistency indirectness imprecision (0.07 to 0.48 HIGH T
higher)
SF36-Physical component (change+final scores) Short Term- Acupuncture vs. waiting list control (Better indicated by higher values): Witt 2005; Witt 2006
higher)
SF36-Physical component (change+final scores) Short Term- Acupuncture vs. supervised osteoarthritis education (change score) (Better indicated by higher values): Berman 2004
a c
1 randomised serious no serious no serious serious none 169 125 - SMD 0.29 higher IMPORTAN
Update 2014
trials inconsistency indirectness (0.06 to 0.52 LOW T
higher)
SF36-Mental component (Final scores)Short Term- Acupuncture vs. waiting list control (Better indicated by higher values): Witt 2004, Witt 2005
higher)
Pain (final scores) Long Term - Acupuncture vs. waiting list control (Better indicated by lower values): Lansdown 2009
c
a
0.54 higher)
Pain (final scores) Long Term - Acupuncture vs. supervised osteoarthritis education (Better indicated by lower values): Berman 2004
a c
lower)
Pain (final scores) Long Term - Acupuncture as an adjunct to exercise based physiotherapy program (including supervised plus home exercises) vs exercise based physiotherapy program
alone (no adjuvant acupuncture) (Better indicated by lower values): Foster 2007
a
1 randomised serious no serious no serious no serious none 108 105 - SMD 0.06 higher CRITICAL
0.33 higher) E
Pain (final scores) Long Term - Acupuncture vs. physician consultations (with a physiotherapy co-intervention) (Better indicated by lower values): Scharf 2006
a c

215
Osteoarthritis
lower)
Function (final scores) Long Term - Acupuncture vs. waiting list control (Better indicated by lower values): Lansdown 2009
a c
1 randomised serious no serious no serious very serious none 15 15 - SMD 0.01 lower CRITICAL
trials inconsistency indirectness (0.73 lower to VERY LOW
0.7 higher)
Function (final scores) Long Term - Acupuncture vs. supervised osteoarthritis education (Better indicated by lower values): Berman 2004
a c
lower)
Function (final scores) Long Term - Acupuncture as an adjunct to exercise based physiotherapy program (including supervised plus home exercises) vs exercise based physiotherapy
program alone (no adjuvant acupuncture) (Better indicated by lower values): Foster 2007
a
1 randomised serious no serious no serious no serious None 113 105 - SMD 0.00 (0.26 CRITICAL
trials inconsistency indirectness imprecision lower to 0.27 MODERAT
higher) E
Function (final scores) Long Term - Acupuncture vs. physician consultations (with a physiotherapy co-intervention) (Better indicated by lower values): Scharf 2006
a c
1 randomised serious no serious no serious serious None 318 307 - SMD 0.5 lower CRITICAL
Update 2014
lower)
Stiffness (change +final scores) Long Term- Acupuncture vs. waiting list control (Better indicated by lower values): Lansdown 2009
a c
1 randomised serious no serious no serious very serious None 15 15 - SMD 0.6 lower CRITICAL
trials inconsistency indirectness (0.78 lower to VERY LOW
0.66 higher)
Stiffness (change +final scores) Long Term - Acupuncture vs. physician consultations (with a physiotherapy co-intervention)(change score) (Better indicated by lower values): Scharf 2006
a c
1 randomised serious no serious no serious serious None 315 309 - SMD 0.43 lower CRITICAL
lower)
EQ5D (final scores) Long Term - Acupuncture vs. waiting list control (Better indicated by higher values): Lansdown 2009
a 11
1 randomised serious no serious no serious very serious None 15 15 - SMD 0.13 higher IMPORTAN
trials inconsistency indirectness (0.58 lower to VERY LOW T
0.85 higher)
SF12 Physical component (change score) Long Term - Acupuncture vs. physician consultations (with a physiotherapy co-intervention) (Better indicated by higher values): Scharf
a c
1 randomised serious no serious no serious serious None 315 309 - SMD 0.37 higher IMPORTAN
higher)
SF12 Mental component (change score) Long Term) - Acupuncture vs. physician consultations (with a physiotherapy co-intervention) (Better indicated by higher values): Scharf 2006
a
1 randomised serious no serious no serious no serious None 315 309 - SMD 0.03 higher IMPORTAN
trials inconsistency indirectness imprecision (0.13 lower to MODERAT T
0.18 higher) E

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SF36 Physical component (change + final scores) Long Term - Acupuncture vs. waiting list control (Better indicated by higher values): Witt 2006
a
1 randomised serious no serious no serious no serious None 165 152 -
SMD 0.86 higher IMPORTAN
trials inconsistency indirectness imprecision (0.62 to 1.09 MODERAT T
higher) E
SF36 Physical component (change +final scores) Long Term - Acupuncture vs. supervised osteoarthritis education (change score) (Better indicated by higher values): Berman 2004
a c
1 randomised serious no serious no serious serious None 169 125 - SMD 0.35 higher IMPORTAN
higher)
SF36 Physical component (change +final scores) Long Term - Acupuncture vs. physician consultations (with a physiotherapy co-intervention) (change score) (Better indicated by higher
values): Scharf 2006
a
trials inconsistency indirectness imprecision (0.13 lower to MODERAT T
0.18 higher) E
SF36 Mental component (final scores) Long Term - Acupuncture vs. waiting list control (Better indicated by higher values): Witt 2006
Update 2014
a
higher) E
OMERACT-OARSI responder criteria ( final scores) Long Term - Acupuncture vs. supervised osteoarthritis education: Berman 2004
a
1 randomised serious no serious no serious no serious None 98/186 52/174 RR 1.76 227 more per IMPORTAN
trials inconsistency indirectness imprecision (52.7%) (29.9%) (1.35 to 1000 (from 105 MODERAT T
2.3) more to 389 E
more)
effects analysis. A sensitivity analysis was conducted on the trials judged to have adequate blinding.

217
Osteoarthritis
Table 123: Acupuncture vs. waiting list control or other active treatments- Hip OA
waiting list or other active Importanc

Relative Quality
No of Risk of Other Acupunctur treatment controls for hip e
Design Inconsistency Indirectness Imprecision (95% Absolute
studies bias considerations e OA post-treatment scores
CI)
analysis
Pain (Time point equal to or less than three months and closest to eight weeks post-randomisation) - Acupuncture vs. waiting list control (Better indicated by lower values): Witt 2006
a
1 randomised serious no serious no serious no serious None 43 32 - SMD 1.64 lower CRITICAL
trials inconsistency indirectness imprecision (2.17 to 1.11 MODERAT
lower) E
Function (Time point equal to or less than three months and closest to eight weeks post-randomisation) - Acupuncture vs. waiting list control (Better indicated by lower values): Witt 2006
a
lower) E
Update 2014
Stiffness (Time point equal to or less than three months and closest to eight weeks post-randomisation) - Acupuncture vs. waiting list control (Better indicated by lower values): Witt 2006
a
lower) E
SF36-Physical component (Time point equal to or less than three months and closest to eight weeks post-randomisation) - Acupuncture vs. waiting list control (Better indicated by higher
values): Witt 2006
a
higher) E
SF36-Mental component (Time point equal to or less than three months and closest to eight weeks post-randomisation) - Acupuncture vs. waiting list control (Better indicated by higher
values): Witt 2006
a b
1 randomised serious no serious no serious serious None 43 32 - SMD 0.24 higher
IMPORTAN
T
0.7 higher)

218
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Evidence from CG59:
One study499 comparing acupuncture plus usual care versus usual care was included in CG59. This
paper has now been supplemented with a more detailed paper from the same study found in the
update search 377,488. This study looked at the cost-effectiveness of acupuncture plus usual care,
compared with usual care. This was a German study with a time horizon of 3 months (follow up and
treatment duration). This is summarised in the economic evidence profile below (Table 124).
An original cost-effectiveness analysis was conducted for CG59 using four RCTs 32,400,404,498 (included in
the original guideline review) comparing acupuncture or electro-acupuncture with sham
Update 2014
acupuncture. WOMAC scores were taken from the RCTs and mapped onto EQ-5D using the formula
from Barton 2008. Only direct costs of the interventions were considered, either a 30 or 20 minute
session with a physiotherapist and the cost of the needles.
A summary of this analysis can be found in Appendix M.
Evidence statements have not been drafted for the CG59 analysis as this has not been updated in this
guideline update, and more weight was placed by the GDG on cost effectiveness and clinical
evidence from the update guideline.
One study488 was found, which looked at the cost effectiveness of acupuncture plus advice and
exercise, compared with advice and exercise. This was a UK study, with a treatment duration of 6
weeks, with a follow up duration of 12 months.
This is summarised in the economic evidence profile below (Table 124). See also the study selection
flow chart in Appendix E and study evidence tables in Appendix H
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Table 124: Economic evidence profile: Acupuncture as an adjunct based on pragmatic trials
Incremental
Incrementa effects Incremental
l cost per (QALYs) per cost per QALY
Reinhold Partially Minor Acupuncture + usual care vs usual care £322 0.0241 £13,354 (d) 85% probability of being cost
377
2009 applicable limitations effective at a threshold of
(Germany) (b) (c) Study is part of the Acupuncture in £20,000 per QALY gained.
499
(a) Routine Care (ARC) studies .
Time horizon was 3 months – the same Sensitivity analysis showed that
as the treatment duration. the parameters which had the
Not stated whether traditional Chinese largest effect were the cost of
acupuncture points are used. acupuncture, and the effect
duration.
Update 2014
Whitehurst Directly Minor Acupuncture + advice and exercise vs £85 (f) 0.022 £3,889 77% probability of being cost
488
2011 (UK) applicable limitations advice and exercise effective at a threshold of
(e) £20,000 per QALY gained.
150
Based on an RCT .
Treatment duration was 6 weeks, but Sensitivity analysis also included
patients were followed up for 12 advice and exercise plus non-
months. penetrating acupuncture in the
Traditional Chinese acupuncture base case. This was found to be
points were used. of similar cost and effect to
acupuncture.
499
(a) This paper provides further detail to the Acupuncture in routine care study (2006) which looked at the effectiveness and cost-effectiveness of acupuncture for various chronic conditions
(OA,low back pain, and headaches). Whereas this paper includes solely the subgroup of OA patients. The cost effectiveness results are therefore the same (reported as €17,845 in the last
guideline as this is the unadjusted figure) because it is the same study, but the Reinhold paper merely goes into more detail about the costs and effects of the OA patients.
(b) German study (costs may not be applicable to UK)
(c) Short time horizon (3 months). SF-36 scores were mapped onto the SF-6D, rather than EQ5D.
(d) Incremental cost and cost effectiveness converted from Euros.
(e) Time horizon could be longer to capture any longer term health effects. Relying on patients to recall healthcare usage.
(f) The incremental cost for Whitehurst is lower (despite the fact that it has a longer time horizon) than the Reinhold because of the comparator. In other words, it does not cost much more
to incorporate acupuncture into the advice and exercise sessions, therefore the cost difference between the two groups is small (as it’s the cost of the sessions which is the main driver for
the total costs). Also bearing in mind that the length of the treatment was only 6 weeks (Reinhold was 3 months), and there wasn’t much difference in resource use between the two
groups over the 12 months.

220
Osteoarthritis
The two studies comparing acupuncture as an adjunct have a similar QALY gain, even though
Whitehurst has a time horizon four times longer than that of Reinhold.
Explanations for this are: the length of the treatment duration (3 months for Reinhold and only 6
weeks for Whitehurst).
The clinical review shows that there was a very small difference in the WOMAC pain score (Table
122) in the Foster trial150 (which is the effectiveness data source for Whitehurst). Thus helping to
explain why the QALY gain is smaller than that of the Reinhold study, despite a longer time horizon.
Clinical
Acupuncture vs. Sham (short term)

 Ten studies with 2290 people with osteoarthritis of the knee suggested that acupuncture and
sham acupuncture may be similarly effective in decreasing pain measured on the WOMAC scale
[LOW].
 Five studies with 800 people with osteoarthritis of the knee suggested that acupuncture may be
clinically more effective than sham acupuncture in decreasing pain measured on the visual
analogue scale (VAS) however there was some uncertainty [VERY LOW].
 One study with 55 people with osteoarthritis of the knee suggested that acupuncture and sham
acupuncture may be similarly effective in decreasing pain measured on the Knee Society Score
[LOW].
Update 2014
 Ten studies with 2285 people with osteoarthritis of the knee suggested that acupuncture and
sham acupuncture may be similarly effective in improving function measured on the WOMAC
scale [LOW ].
acupuncture may be similarly effective in improving function measured on the Knee Society score
[LOW].
 Six studies with 603 people with osteoarthritis of the knee suggested that acupuncture and sham
acupuncture may be similarly effective in decreasing stiffness measured on the WOMAC scale
[VERY LOW].
acupuncture may be similarly effective in improving quality of life measured on the EuroQoL
[LOW].
 One study with 455 people with osteoarthritis of the knee showed that acupuncture and sham
acupuncture may be similarly effective in improving quality of life (measured on the physical
subscale of SF12) [HIGH].
acupuncture may be similarly effective in improving quality of life (measured on the mental
 Two studies with 556 people with osteoarthritis of the knee showed that acupuncture and sham
subscale of SF36), [HIGH].
 One with 218 people with osteoarthritis of the knee suggested that acupuncture and sham
Osteoarthritis
Acupuncture vs. Sham (Long term)

 Four studies with 1400 people with osteoarthritis of the knee suggested that acupuncture and
sham acupuncture may be similarly effective in decreasing pain measured on the WOMAC scale
[HIGH].
 Four studies with 1400 people with osteoarthritis of the knee showed that acupuncture and sham
acupuncture may be similarly effective at improving function measured on the WOMAC scale
[HIGH].
 Two studies with 896 people with osteoarthritis of the knee suggested that acupuncture and
sham acupuncture may be similarly effective at improving stiffness measured on the WOMAC
scale [HIGH].
 Two studies with 501 people with osteoarthritis of the knee suggested that acupuncture and
sham acupuncture may be similarly in improving quality of life (measured on the physical subscale
of SF36) [HIGH].
 One with 218 people with osteoarthritis of the knee suggested that acupuncture and sham
Update 2014
acupuncture may be similarly effective at improving responder rate on the OMERACT-OARSI
criteria, [LOW].
 One study with 52 people with osteoarthritis of the hip suggested that acupuncture and sham
acupuncture may be similarly effective in decreasing pain measured on the WOMAC scale [LOW].
 One study with 52 people with osteoarthritis of the hip suggested that acupuncture and sham
acupuncture may be similarly effective in improving function measured on the WOMAC scale
[LOW].
Acupuncture vs. waiting list control or other active treatment (short term)
 Seven studies with 893 people with osteoarthritis of the knee showed that acupuncture was
clinically more effective than waiting list control in decreasing pain measured on the WOMAC pain
scale [LOW].
 One study with 294 people with osteoarthritis of the knee suggested that acupuncture was
clinically more effective than supervised osteoarthritis education in decreasing pain measured on
the WOMAC pain scale, but there was some uncertainty. [LOW].
 One study with 218 people with osteoarthritis of the knee suggested that as an adjunct to
exercise-based physiotherapy and exercise- based physiotherapy alone may be similarly effective
in decreasing pain measured on the WOMAC pain scale [LOW].
 One study with 121 people with osteoarthritis of the knee suggested that acupuncture and home
exercise and advice leaflet may be similarly effective in decreasing pain measured on the WOMAC
pain scale [LOW].
Osteoarthritis
 One study with 120 people with osteoarthritis of the knee suggested that acupuncture and
supervised exercise alone may be similarly effective in decreasing pain measured on the WOMAC
pain scale [MODERATE].
 One study with 624 people with osteoarthritis of the knee suggests that acupuncture may be
more clinically effective than physician consultations with a physiotherapy co-intervention in
decreasing pain measured on the WOMAC pain scale, but there was some uncertainty [LOW].
 One study with 16 people with osteoarthritis of the knee suggested that acupuncture and TENS
may be similarly effective in decreasing pain measured on the WOMAC pain scale[LOW].
acupuncture with TENS may be similarly effective in decreasing pain measured on the WOMAC
pain scale [VERY LOW].
may be clinically more effective than waiting list control in decreasing pain measured on the
WOMAC pain scale, but there was some uncertainty [VERY LOW].
 One study with 16 people with osteoarthritis of the knee suggested that acupuncture with TENS
and TENS alone may be similarly effective in decreasing pain measured on the WOMAC pain scale
[VERY LOW].
 Three studies with 261 people with osteoarthritis of the knee suggested that acupuncture may be
clinically more effective than waiting list control in decreasing pain measured on a VAS scale, but
there was some uncertainty [VERY LOW].
Update 2014
exercises + advice leaflet may be similarly effective at decreasing pain measured on a VAS scale
result [LOW].
supervised exercise may be similarly effective at decreasing pain measured on a VAS scale [LOW].
 One study with 16 people with osteoarthritis of the knee suggested that acupuncture may be
clinically more effective than TENS in decreasing pain measured on a VAS scale, but there was
some uncertainty [VERY LOW].
acupuncture + TENS may be similarly effective in decreasing pain measured on a VAS scale [VERY
LOW].
and waiting list control may be similarly effective in decreasing pain measured on a VAS scale, but
may be clinically more effective than TENS alone in decreasing pain measured on a VAS scale, but
 Five studies with 852 people with osteoarthritis of the knee suggested that acupuncture may be
clinically more effective than waiting list control in improving function as measured with the
WOMAC function scale, [LOW].
more clinically effective than supervised osteoarthritis education in improving function as
measured with the WOMAC function scale, but there was some uncertainty [LOW].
 One study with 218 people with osteoarthritis of the knee suggested that acupuncture + exercise-
based physiotherapy program and an exercise-based physiotherapy program alone may be
similarly effective at improving function as measured with the WOMAC function scale
[MODERATE].
Osteoarthritis
exercise or advice leaflet may be similarly effective at improving function as measured with the
WOMAC function scale[LOW].
 In one study with 120 people with osteoarthritis of the knee acupuncture and supervised exercise
may be similarly effective at improving function as measured with the WOMAC function scale
[MODERATE].
 One study with 623 people with osteoarthritis of the knee showed that acupuncture was clinically
more effective than physician consultations with a physiotherapy co-intervention in improving
function as measured with the WOMAC function scale [MODERATE].
 Four studies with 579 people with osteoarthritis of the knee showed that acupuncture was
clinically more effective than waiting list control at improving stiffness as measured with the
WOMAC stiffness scale [VERY LOW].
clinically more effective than waiting list control at improving function as measured with the
Lequesne Index, but there was some uncertainty [HIGH].
 One study with 30 people with osteoarthritis of the knee suggested that acupuncture and waiting
list control may be similarly effective at improving quality of life measured by EQ5D [VERY LOW].
waiting list control may be similarly effective at improving quality of life measured by SF12-
physical component, [MODERATE].
Update 2014
waiting list control may be similarly effective at improving quality of life measured by SF12-
mental component, [HIGH].
 Two studies with 499 people with osteoarthritis of the knee shows that acupuncture was clinically
more effective than waiting list control at improving quality of life measured by SF36 physical
component [HIGH].
supervised osteoarthritis education may be similarly effective at improving quality of life
measured by SF36 Physical component, [LOW].
 Two studies with 499 people with osteoarthritis of the knee showed that acupuncture and waiting
list control may be similarly effective at improving quality of life measured by SF36-Mental
component at follow up of less than three months from baseline, but [HIGH].
Acupuncture vs. waiting list control or other active treatment (Long term)
list control may be similarly effective in reduction of pain measured by WOMAC pain [VERY LOW].
clinically more effective than supervised osteoarthritis education in reduction of pain measured
by WOMAC Pain scale, but there was some uncertainty [LOW].
 One study with 213 people with osteoarthritis of the knee suggests that acupuncture and
exercise- based physiotherapy compared to exercise-based physiotherapy alone are similarly
effective at reducing pain measured by WOMAC pain scale [MODERATE].
clinically more effective than physician consultation with a physiotherapy co-intervention in
reduction of pain measured by WOMAC Pain scale but there is some uncertainty [LOW].
Osteoarthritis
list control may be similarly effective in improving function measured by WOMAC function scale
[VERY LOW].
clinically more effective than supervised osteoarthritis education at improving function measured
by WOMAC function scale but there was some uncertainty [LOW].
exercise based physiotherapy and exercise based physiotherapy program alone are similarly
effective at improving function measured by WOMAC function scale [MODERATE].
clinically more effective than physician consultations with a physiotherapy co-intervention at
improving function measured by WOMAC function scale, but there was some uncertainty [LOW].
list control may be similarly effective at improving stiffness measured by WOMAC stiffness scale
[VERY LOW ].
physician consultations with a physiotherapy co-intervention may be similarly effective at
improving stiffness measured by WOMAC Stiffness scale, but [LOW].
list control are similarly effective at improving quality of life as measured by EQ5D [VERY LOW].
physician consultations with a physiotherapy co-intervention may be similarly effective in
Update 2014
improving quality of life as measured with the SF12 Physical component, but there was some
uncertainty [LOW].
physician consultations with a physiotherapy intervention are similarly effective at improving
quality of life measured by SF12 Mental component [MODERATE].
more effective than waiting list control in improving quality of life measured by SF36 Physical
component [MODERATE].
 One study with 294 people with osteoarthritis of the knee showed that and supervised
osteoarthritis education may be similarly effective in improving quality of life measured by SF36
Physical component [LOW].
physician consultations with a physiotherapy co-intervention was similarly effective at improving
quality of life measured by SF36 Physical component [MODERATE].
waiting list control may be similarly effective in improving quality of life measured by SF36 Mental
component, [MODERATE].
more effective than supervised osteoarthritis education in improving OMERACT-OARSI responder
rate although there was some uncertainty [MODERATE].
Hip OA
 One study with 75 people with osteoarthritis of the hip showed that acupuncture was clinically
more effective that waiting list control in reducing pain measured with the WOMAC pain scale at
follow up of less than three months from baseline [MODERATE].
Osteoarthritis
more effective that waiting list control in improving function measured with the WOMAC function
scale at follow up of less than three months from baseline [MODERATE].
more effective that waiting list control in improving joint stiffness measured with the WOMAC
stiffness scale at follow up of less than three months from baseline [MODERATE].
more effective that waiting list control in improving quality of life measured by SF36 Physical
component at follow up of less than three months from baseline [MODERATE].
 One study with 75 people with osteoarthritis of the hip suggested that acupuncture and waiting
list control may be similarly effective in improving quality of life measured by SF36 mental
component at follow up of less than three months from baseline, but [LOW].
Economic
 One cost-utility analysis found that acupuncture + usual care compared with usual care was cost
effective (£13,354 per QALY gained). This study was assessed as partially applicable with minor
limitations.
 One cost-utility analysis found that acupuncture + advice and exercise compared with advice and
exercise was cost effective (£3,889 per QALY gained). This study was assessed as directly
applicable with minor limitations.
Update 2014
Recommendations 17.Do not offer acupuncture for the management of osteoarthritis. [2014]
Relative values of The GDG considered pain and function to be the critical outcomes for
different decision-making. Other important outcomes were stiffness, OMERACT OARSI
outcomes responder criteria and the patient’s global assessment.
Trade-off between The GDG considered the comparison of acupuncture to sham acupuncture to
clinical benefits be the most appropriate clinical comparison to assess the benefits and harms
and harms of acupuncture. Results were stratified by joint and data were available on
knee and hip for this review.
In looking at interventions appropriate controls are needed. When the GDG

considered the evidence for the efficacy of a given therapy, the primary
comparison for decision making involved looking at active therapies versus
placebo, and in the case of device studies versus sham control. They then
also considered other comparators where placebo or sham were not
available or inappropriate, such as when looking at toxicity and cost
effectiveness.
The GDG understand and were aware of the considerable effect size of
contextual response in clinical trials and in practice for all therapies. Where
possible we tried to discern the specific treatment efficacy element that
relates to the treatment rather than contextual response. Where such trials
exist as to allow for the effective measurement of contextual response they
must form the primary comparator for decision making, to ensure we are
recomending a therapy with a scientifically proven treatment response. The
Osteoarthritis
GDG therefore believe that sham is the appropriate comparator to elicit the
specific treatment efficacy for acupuncture.
Knee OA
No clinically important difference was found between acupuncture and sham

acupuncture in OA of the knee in the critical outcomes of pain reduction
(WOMAC scale, and the knee pain severity score), functional improvement
(WOMAC and function knee society score) and reduction of stiffness
(WOMAC stiffness scale) at short and long term time points. (Short term-
time points less than 3 months and closest to 8 weeks after baseline and long
term- time points greater than or equal to 26 weeks after baseline). This
finding remained in a sensitivity analysis, which assessed only studies that
had conducted adequate blinding.
Five studies suggested that acupuncture may be clinically more effective

than sham acupuncture in decreasing pain measured on a visual analogue
scale (VAS) at short term time points, however there was some uncertainty
surrounding this effect and when selecting those studies which had adequate
blinding this effect disappeared and no clinically important difference
between acupuncture and sham acupuncture was demonstrable.
Hip OA
No clinically important difference was found between acupuncture and sham
Update 2014
acupuncture in OA of the hip in the critical outcomes of pain reduction (VAS)
or functional improvement (Lequesne index).
Overall, even though there was no evidence that acupuncture was harmful,
the efficacy data failed to reach the level of a clinically important difference
of acupuncture over sham acupuncture. This led the GDG to support a ‘do
not offer acupuncture’ recommendation.
Economic It is widely accepted that large pragmatic randomised trials are the best
considerations study design on which to base an economic evaluation, as this will capture
the cost-effectiveness of an intervention as it would be used in practice,
compared to what is currently standard care or in addition/as an adjunct to
standard care. The cost-effectiveness of acupuncture versus sham
acupuncture is not of interest, since we are interested in the benefits and
opportunity costs that would occur in practice. Furthermore the incremental
cost of acupuncture versus sham acupuncture could be zero, since the staff
time, etc involved would most likely be the same.
However, an intervention must first be shown to have a clinical benefit, and

the best comparator to prove this would be a placebo or sham where
possible in order to identify the magnitude of effect over and above the
contextual or placebo response. Only if effect has been proven above
placebo/sham, should cost-effectiveness evidence looking at an intervention
as an adjunct be considered.
The CG59 analysis was based on a sham comparison. However given that no
costs were included in the sham acupuncture arm, then this should be
interpreted as a comparison with usual care, but using sham acupuncture
controlled trials. 3 out of 4 studies from the analysis showed acupuncture
Osteoarthritis
was not cost effective. This analysis was not updated in this guideline update
and was rated as having potentially serious limitations.
As mentioned above, economic evaluations based on pragmatic trials are

preferred, therefore more weight was placed on the two economic
evaluations (based on pragmatic trials) identified from the update search:
 Reinhold (2009) compared acupuncture + usual care with usual care,

and found that acupuncture was cost effective (£13,354 per QALY
gained). This study was assessed as partially applicable with minor
limitations.
 Whitehurst (2011) compared acupuncture + advice and exercise with
advice and exercise and found that acupuncture was cost effective
(£3,889 per QALY gained). This study was assessed as directly
applicable with minor limitations.
Although there was evidence that acupuncture was cost effective as an

adjunct, the GDG hypothesised that could have been down to the contextual
effects (e.g. the additional interaction time from the acupuncture), rather
than the needling.
In summary, although pragmatic trials are the most suitable to assess the
cost-effectiveness of any health intervention, it is also reasonable to expect
that each intervention has a proven clinical effect over and above any
Update 2014
contextual effect. As noted above this has not yet been proven in the case of
acupuncture for osteoarthritis.
Quality of One Cochrane review on the use of acupuncture for the management of
evidence peripheral joint arthritis was identified and was updated as part of this
review. In addition, six RCTs were identified since the publication of the
Cochrane review. The Cochrane review only included studies that concerned
exclusively participants with OA of one or more of the peripheral joints (i.e.
knee, hip, and hand). The Cochrane review included 16 RCTs. Of these, 10
RCTs compared acupuncture to sham acupuncture. Nine of these RCTs were
in people with OA of the knee and one was in people with OA of the hip.
Knee
Acupuncture vs. sham
Ten studies were included; and the following outcomes were reported at
short term: WOMAC pain, VAS pain, Knee Society Score pain, , WOMAC
function, KSS function, WOMAC stiffness, and EUROQOL, which all ranged
from very low to low quality evidence. For SF12 and SF36, the evidence
ranged from moderate to high quality. Acupuncture and sham acupuncture
were similarly effective for all outcomes.
Outcomes that were reported at long term follow up were: WOMAC Pain,
WOMAC function, WOMAC stiffness, SF12, SF36. These all ranged from
moderate to high quality evidence and OMERACT-OARSI responder criteria
was of low quality.
The main limitation was that there was ineffective blinding of sham
acupuncture in three studies, and the effect of this was investigated by
Osteoarthritis
carrying out sensitivity analysis. The results of the sensitivity analysis are
discussed above in the trade off between clinical benefits and harms section
for each individual joint
An Individual Patient Data (IPD) meta-analysis 474 was also identified. This IPD
involved analysis of acupuncture vs. sham acupuncture and acupuncture vs.
no acupuncture on people with OA. This analysis included only high quality
studies with adequate allocation concealment and studies that reported
results at more than 4 weeks follow up. Where applicable the effect sizes
were transposed into our own meta-analysis to provide the most accurate
estimate of overall effect size. Risk of bias was assessed with GRADE on the
basis of the evidence for an outcome across studies.
Acupuncture vs. waiting list control or other active treatment
Overall, eleven studies compared acupuncture to waiting list control or other

active treatment. The short term efficacy outcomes of WOMAC pain, VAS
pain, WOMAC function WOMAC stiffness and Lequesne index were all of low
or very low quality; all of the efficacy outcomes apart from Lequesne index
indicated that acupuncture was more clinically effective than waiting list
control. The remaining quality of life outcomes of SF12 and SF36 were of
moderate and high quality and all apart from the mental health component
of SF36 indicated that people who had acupuncture had an increased quality
of life compared to waiting list controls. For long term outcomes, WOMAC
Update 2014
pain, function, stiffness and EQ5D were all low or very low quality outcomes
and indicated no difference between acupuncture and waiting list. Long term
follow up SF36 outcomes were of high quality and indicated that
acupuncture groups had a higher quality of life than waiting list control.
For all other active treatment comparisons there was only one study
included for each comparison. Acupuncture was compared to supervised
exercise, supervised OA education, exercise and physiotherapy program,
home exercise/ advice leaflet and physician consultation. WOMAC pain and
function outcomes were reported for all of the comparisons listed, and the
quality of the evidence for these outcomes was either moderate or low. For
active comparisons, such as exercise and physiotherapy, the acupuncture
group and the comparison group tended to be similarly clinically effective.
For comparisons such as education and physician consultation, the
acupuncture group appeared to gain more clinical benefit than the
comparison group.
One very small study215 assessed acupuncture+/- TENS vs. TENS or waiting
list control in a three arm trial. Short term outcomes of WOMAC pain and
VAS pain were reported and the evidence was either low or very low quality
The individual patient data meta- analysis mentioned above also conducted
an IPD meta-analysis on acupuncture vs. no acupuncture in people with OA.
Hip
One study compared acupuncture to sham acupuncture. Both VAS pain and
function outcomes were of low quality and showed no clinical difference
between acupuncture and sham acupuncture. The study had a high number
of dropouts and ITT analysis was not conducted.
Osteoarthritis
One study compared acupuncture to waiting list control. Short term

outcomes were reported for pain, function, stiffness and SF36 Physical and
Mental components. SF36 Mental component was low quality, all other
outcomes were moderate quality. All outcomes favoured acupuncture,
though with uncertainty around the point estimate. It was unclear whether
the study was blinded and whether participants received the same co-
interventions.
Other The co-opted acupuncturist expert pointed out that the majority of the
considerations evidence base in acupuncture use Chinese acupuncture points within a
Western medicine context. Although the selection of needling points may
follow the traditional Chinese system, the majority of studies in the literature
described the delivery of the whole acupuncture session using a Western
medicine approach to the diagnosis and patient experience of the effects of
the acupuncture. The GDG therefore felt that the included studies were
applicable to acupuncture practices in the UK.
The GDG discussed the fact that although there was some evidence
supporting acupuncture it generally came from lower quality evidence. There
was concern over the issues of blinding of participants and the GDG also
noted the findings of sensitivity analyses conducted to determine whether
this impacted on outcome measurement. They particularly noted that the
Update 2014
finding from the limited evidence which reported acupuncture as possibly
being clinically more effective than sham acupuncture, in decreasing as pain
measured on the visual analogue scale (VAS) for knee OA at short term time
points, disappeared when sensitivity analysis was conducted related to
adequate blinding, and no clinically important difference between
acupuncture and sham acupuncture was then demonstrable.
In light of the above, the GDG discussed the effect that the contextual factors
of the provision of acupuncture, such as of increased clinician interaction
time and exercise, may have in addition to the actual needling. The GDG
agreed that it was therefore difficult to determine the efficacy of
acupuncture beyond the contextual effect, and this factor also contributed to
the above recommendation. The GDG did not feel it appropriate to make a
recommendation for the use of acupuncture in OA when it was uncertain
about its clinical effectiveness in the first instance, although the health
economics evidence indicated that acupuncture was cost-effective as an
adjunct.
There was no new evidence to consider as a result of the research

recommendation made in the last guideline which sought to establish
whether a specific group of people would particularly benefit from this
intervention to inform a future recommendation and therefore the GDG
could not be more specific in their recommendation in this regard.
The GDG agreed to draft a research recommendation on identification of

predictors of response to individual treatments in people with osteoarthritis.
For further details on research recommendations, see Appendix N.
Osteoarthritis
8.6 Aids and devices

Walking aids are commonly prescribed for hip and knee OA and their mechanism of efficacy is
assumed to be via a biomechanical effect. Chan et al conducted a small trial of cane use (on either
side) and examined walking speed and cadence as mediators of effect64. Van der Esch et al identified
that 44% of an OA cohort possessed a walking aid (commonly canes), and that being older and
greater pain and disability were determinants of use470. Non-use is associated with negative views of
walking aids, suggesting that careful attention is needed to prescription and discussing clients’
attitudes to cane use.
People with more severe hip and knee OA are commonly provided with or obtain long-handled
reachers, personal care aids (eg sock aids to reduce bending), bath aids, chair and bed raisers, raised
toilet seats, perch stools, half steps and grab rails, additional stair rails and may also have home
adaptations to improve access internally and externally. Wielandt et al highlighted the importance of
carefully matching assistive devices to the patients’ needs489. Factors significantly associated with
assistive technology (AT) non-use are: poor perceptions of AT and their benefits; anxiety; poor ability
to recall AT training; poor perception of disability/illness; and lack of choice during the selection
process. Many people do obtain AT without professional advice and may waste money if their choice
is inappropriate due to lack of information.
Splints are commonly used for hand problems, especially OA of the thumb base. Practical advice is
given to balance activity and rest during hand use; to avoid repetitive grasp, pinch and twisting
motions; and to use appropriate assistive devices to reduce effort in hand function (eg using enlarged
grips for writing, using small non-slip mats for opening objects, electric can openers).
Footwear, bracing and walking aids
We looked for studies that investigated the efficacy and safety of aids and devices compared to other
aids and devices or no intervention/usual care with respect to symptoms, function, quality of life.
One Cochrane systematic review and meta-analysis50 was found on braces and insoles and 20
additional RCTs19,33,51,64,96,190,191,201,331,359,366,382,451-455,479,485,486 were found on shoes, insoles, canes,
braces, strapping, splinting and taping. Two of these studies452,453 were reports of the same RCT,
showing mid-study results452 and end-of study results453. One study359 reports the long-term results
of an RCT273 (mid-study results) that was included in the Cochrane systematic review. Five
RCTs33,190,201,382,486 were excluded due to methodological limitations. Therefore overall, 12 RCTs were
found in addition to the Cochrane review.
The Cochrane MA50 included 4 RCTs (with N=444 participants) that on insoles and braces in people
with knee osteoarthritis. Studies were all randomised, parallel-group design but were inadequately
blinded (single blind or blinding not mentioned). The RCTs included in the analysis differed with
respect to:
 Interventions and comparisons
 Trial size, length, follow-up and quality.
Osteoarthritis
The Cochrane meta-analysis assessed the RCTs for quality and pooled together all data for the
outcomes of symptoms and function. However, the outcome of quality of life was not reported
because quality of life was not assessed by the individual RCTs included in this systematic review.
The 13 RCTs not included in the Cochrane systematic review differed with respect to:
 osteoarthritis site (11 RCTs knee, 2 RCTs thumb)
 Trial size, blinding, length and follow-up.
Assistive devices
We looked for studies that investigated the efficacy and safety of assistive devices versus no devices
with respect to symptoms, function and quality of life in adults with osteoarthritis. 1 RCT430 was
found on assistive devices and assessed the outcomes of pain and function. Four additional
observational studies280,436,440,472 were found on usage and assessment of the effectiveness of
assistive devices.
The included RCT was a randomised, single-blind parallel group study.
The 4 observational studies differed with respect to osteoarthritis site, study design, sample size and
outcomes measured.
8.6.3 Evidence statements: footwear, bracing and walking aids
Table 125: Symptoms:pain

Knee
Brace
50
Pain on function (6 1 MA , 1 RCT, Knee brace vs 6 months Knee brace better
minute walk test, 30 sec N=119 neoprene sleeve
stair-climb test).
50
Pain on function (6 1 MA , 1 RCT, Knee brace vs 6 months Knee brace better
minute walk test, 30 sec N=119 medical treatment
stair-climb test)
50
Pain on function (6 1 MA , 1 RCT, Neoprene sleeve 6 months Neoprene sleeve
minute walk test, 30 sec N=119 vs medical better
stair-climb test) treatment
51
Pain severity (VAS) 1 RCT (N-=118) Knee brace + 3 months, 6 NS
conservative months, 12
treatment vs months or
control overall.
(conservative
treatment)
Insoles
50
WOMAC Pain 1 MA , 1 RCT, laterally wedged 1 month, 3 NS
N=147 insole vs neutrally months and 6
wedged insole months
Osteoarthritis

follow-up
19
WOMAC Pain; Overall 1 RCT (N=90) laterally wedged 6 weeks (end NS
pain (VAS); Clinical insole vs neutrally of treatment)
improvement in wedged insole
WOMAC pain (score ≥50
points); Pain
improvement in patients
with KL grade 4
compared to KL grade
<4; Pain improvement in
patients with BMI <30
kg/m2 compared to
patients with BMI ≥30
kg/m2
50
Pain (VAS) 1 MA , 1 RCT, subtalar strapped 8 weeks NS
N=90 insole vs inserted
insole
359
WOMAC Pain (change 1 RCT (N=156) laterally wedged 2 years (end NS
from baseline) insole vs neutrally of treatment)
wedged insole
Taping
96
Daily Pain, VAS 1 RCT (N=14) Medial taping vs 4 days, end of p<0.05
neutral taping treatment Favours medial
taping
96
Patient’s change scores 1 RCT (N=14) Medial taping vs 4 days, end of p<0.05
(Number of patients neutral taping treatment Favours medial
‘better’) taping
96
Pain on standing, VAS 1 RCT (N=14) Medial taping vs 6 months, end -1.2 (medial) and -
(change from baseline) neutral taping of treatment 0.3 (neutral)
medial taping
better
96
Daily Pain, VAS 1 RCT (N=14) Medial taping vs 4 days, end of p<0.05
lateral taping treatment Favours medial
taping
96
Patient’s change scores 1 RCT (N=14) Medial taping vs 4 days, end of p<0.05
(Number of patients lateral taping treatment Favours medial
‘better’) taping
96
Pain on standing, VAS 1 RCT (N=14) Medial taping vs 6 months, end -1.2 (medial) and -
(change from baseline) lateral taping of treatment 0.3 (neutral)
medial taping
better
191
Pain on movement, VAS 1 RCT (N=87) therapeutic tape 3 weeks, end 3 weeks: -2.1
(change from baseline) vs control tape of treatment (therapeutic) and –
and 3 weeks 0.7 (neutral)
post- 3 weeks post-
treatment treatment -1.9
(therapeutic) and –
1.1 (control)
Therapeutic tape
Osteoarthritis

better
191
Pain on worst activity, 1 RCT (N=87) therapeutic tape 3 weeks, end 3 weeks: -2.5
VAS (change from vs control tape of treatment (therapeutic) and –
baseline) and 3 weeks 1.1 (neutral)
post- 3 weeks post-
1.4 (control)
Therapeutic tape
better
191
WOMAC Pain (change 1 RCT (N=87) therapeutic tape 3 weeks, end 3 weeks: -1.8
from baseline) vs control tape of treatment (therapeutic) and –
1.6 (neutral)
Therapeutic tape
better
191
Knee Pain Scale, KPS, 1 RCT (N=87) therapeutic tape 3 weeks, end 3 weeks: -2.7
Severity (change from vs control tape of treatment (therapeutic) and –
baseline) 1.9 (neutral)
Therapeutic tape
better
191
Frequency (change vs control tape of treatment (therapeutic) and –
from baseline) 2.4 (neutral)
Therapeutic tape
better
191
from baseline) vs control tape of treatment (therapeutic) and –
2.0 (neutral)
Control tape
better
191
Severity (change from vs control tape of treatment (therapeutic) and –
baseline) 2.9 (neutral)
Control tape
better
191
Frequency (change vs control tape of treatment (therapeutic) and –
from baseline) 3.3 (neutral)
Control tape
better
191
Pain on movement, VAS 1 RCT (N=87) therapeutic tape 3 weeks, end 3 weeks: -2.1
(change from baseline) vs no tape of treatment (therapeutic) and
and 3 weeks +0.1 (no tape)
post- 3 weeks post-
0.1 (none)
Therapeutic tape
better
Osteoarthritis

191
Pain on worst activity, 1 RCT (N=87) therapeutic tape 3 weeks, end 3 weeks: -2.5
VAS (change from vs no tape of treatment (therapeutic) and -
baseline) and 3 weeks 0.4 (no tape)
post- 3 weeks post-
0.4 (none)
Therapeutic tape
better
191
from baseline) vs no tape of treatment (therapeutic) and -
and 3 weeks 0.1 (no tape)
post- 3 weeks post-
(therapeutic) and
+0.4 (none)
Therapeutic tape
better
191
Severity (change from vs no tape of treatment (therapeutic) and
baseline) and 3 weeks 0.0 (no tape)
post- 3 weeks post-
(therapeutic) and
+0.5 (none)
Therapeutic tape
better
191
Frequency (change vs no tape of treatment (therapeutic) and -
from baseline) and 3 weeks 0.1 (no tape)
post- 3 weeks post-
0.1 (none)
Therapeutic tape
better
Shoes
331
WOMAC Pain total 1 RCT (N=125) Masai Barefoot 12 weeks (end NS
(change from baseline) Technology (MBT) of treatment)
Shoe vs high-end
walking shoe
331
WOMAC Pain walking 1 RCT (N=125) Masai Barefoot 12 weeks (end NS
Shoe vs high-end
walking shoe
331
WOMAC Pain stairs 1 RCT (N=125) Masai Barefoot 12 weeks (end NS
Shoe vs high-end
walking shoe
Mixed
Osteoarthritis

366
Pain, VAS (change from 1 RCT (N=87) taping + exercises 5 months (3 NS
baseline) + posture months post-
correction + treatment)
education vs and at 12
standard months (10
treatment (no months post-
experimental treatment).
intervention)
452
Pain, VAS (change from 1 RCT (N=66) urethane insole + 3 months, 3 months: -16.4
baseline) strapping + NSAID mid-study (urethane insole)
vs rubber insole + and at 6 and –2.8 (rubber
NSAID months, mid- insole)
study 6 months: -17.3
(urethane insole)
and –3.6 (rubber
insole).
Urethane insole +
strapping + NSAID
better
Hand (Thumb – CMC joint)
479
Pain, VAS (change from 1 RCT (N=40) thumb strap splint 2 weeks (mid- NS
baseline) + abduction treatment)
exercises vs and at 6
control (short weeks (end of
opponens splint + treatment
pinch exercises
485
Pain, VAS (change from 1 RCT (N=26) short opponens 1 week (end NS
baseline); Splint/pinch splint vs long of treatment)
Pain, VAS (change from opponens splint
baseline)
Table 126: Symptoms: stiffness

Knee
Insoles
50
WOMAC Stiffness 1 MA , 1 RCT, laterally wedged 1 month, 3 NS
N=147 insole vs neutrally months and 6
follow-up
359
WOMAC Stiffness 1 RCT (N=156) laterally wedged 2 years (end NS
insole vs neutrally of treatment)
wedged insole
Shoes
331
WOMAC Stiffness 1 RCT (N=125) Masai Barefoot 12 weeks (end NS
Shoe vs high-end
Osteoarthritis

walking shoe
Table 127: Symptoms: function

Knee
Brace
50
WOMAC score 1 MA , 1 RCT, Knee brace vs 6 months Knee brace better
N=119 neoprene sleeve
50
WOMAC score; MACTAR 1 MA , 1 RCT, Knee brace vs 6 months Knee brace better
score N=119 medical treatment
50
WOMAC score 1 MA , 1 RCT, Neoprene sleeve 6 months Neoprene sleeve
N=119 vs medical better
treatment
51
Walking distance 1 RCT (N-=118) Knee brace + 3 months, 12 3 months (Effect
conservative months and size 0.3; p=0.03)
treatment vs overall. 12 months (Effect
control size 0.4; p=0.04)
(conservative Overall (Effect size
treatment) 0.4; p=0.02)
Favours knee
brace
51
Walking distance 1 RCT (N-=118) Knee brace + 6 months NS
conservative
treatment vs
control
(conservative
treatment)
51
Knee function (HSS) at 1 RCT (N-=118) Knee brace + 3 months, 6 NS
conservative months, 12
control overall
(conservative
treatment)
Insoles
50
WOMAC Physical 1 MA , 1 RCT, laterally wedged 1 month, 3 NS
function N=147 insole vs neutrally months and 6
follow-up
19
WOMAC disability; 50- 1 RCT (N=90) laterally wedged 6 weeks (end NS
foot walk time; 5 chair insole vs neutrally of treatment)
stand time. wedged insole
50
Lequesne’s Index; FTA 1 MA , 1 RCT, subtalar strapped 8 weeks NS
angle, talocalcaneal N=90 insole vs inserted
Osteoarthritis

angle and talar tilt angle. insole
50
FTA angle and talar tilt 1 MA , 1 RCT, subtalar strapped 8 weeks P<0.05
angle N=90 insole vs no insole Favours strapped
insole
50
FTA angle; Aggregate 1 MA 1 RCT, N=88 subtalar strapped 8 weeks NS
score. insole vs sock-type
insole
359
WOMAC Function 1 RCT (N=156) laterally wedged 2 years (end NS
(change from baseline) insole vs neutrally of treatment)
wedged insole
Taping
191
Restriction of activity, 1 RCT (N=87) therapeutic tape 3 weeks, end 3 weeks: -1.5
baseline) 1.4 (control)
Therapeutic tape
better
191
WOMAC Physical 1 RCT (N=87) therapeutic tape 3 weeks, end 3 weeks: -4.0
function (change from vs control tape of treatment (therapeutic) and –
Therapeutic tape
better
191
3 weeks post-
treatment: -3.4
6.0 (control)
Control tape
better
191
VAS (change from vs no tape of treatment (therapeutic) and
baseline) and 3 weeks +0.2 (no tape)
post- 3 weeks post-
(therapeutic) and
+0.1 (none)
Therapeutic tape
better
191
WOMAC Physical 1 RCT (N=87) therapeutic tape 3 weeks, end 3 weeks: -4.0
function (change from vs no tape of treatment (therapeutic) and
baseline) and 3 weeks +1.7 (no tape)
post- 3 weeks post-
(therapeutic) and
+1.9 (none)
Therapeutic tape
Osteoarthritis

better
Shoes
331
WOMAC total (change 1 RCT (N=125) Masai Barefoot 12 weeks (end NS
from baseline); Technology (MBT) of treatment)
WOMAC Physical Shoe vs high-end
function (change from walking shoe
baseline); ROM
extension, degrees
(change from baseline);
ROM flexion, degrees
(change from baseline)
Cane
64
Walking speed, m/s 1 RCT (N=14) Ipsilateral cane vs Immediate p=0.00
no cane (unaided Favours cane
walking)
64
Cadence, steps/min 1 RCT (N=14) Ipsilateral cane vs Immediate P<0.001
no cane (unaided Favours cane
walking)
64
Stride length 1 RCT (N=14) Ipsilateral cane vs Immediate NS
no cane (unaided
walking)
64
Walking speed, m/s 1 RCT (N=14) Contralateral cane Immediate p=0.00
vs no cane Favours cane
(unaided walking)
64
Cadence, steps/min 1 RCT (N=14) Contralateral cane Immediate P<0.001
vs no cane Favours cane
(unaided walking)
Mixed
366
WOMAC function 1 RCT (N=87) taping + exercises 5 months (3 NS
(change from baseline) + posture months post-
correction + treatment)
education vs and at 12
standard months (10
treatment (no months post-
intervention)
451
Lequesne’s Index of 1 RCT (N=84) Urethane insoles + 4 weeks, end p=0.001
disease severity, % strapping + NSAID of treatment Favours Urethane
remission vs rubber insoles + insole + strapping
strapping + NSAID + NSAID
455
disease severity, % strapping + NSAID of treatment
remission worn for the
medium length of
time (5-10
hrs/day) vs short-
length (<5
hrs/day),
455
Osteoarthritis

remission worn for the
medium length of
time (5-10
hrs/day) vs long
length (>10
hrs/day),
454
Lequesne’s index of 1 RCT (N=62) insoles + strapping 2 weeks, end NS
disease severity + NSAID - insoles of treatment
(change from baseline). at different
elevations (8 mm
vs 12 mm vs 16
mm)
454
Lequesne’s index of 1 RCT (N=62) 12mm insole + 2 weeks, end p=0.029
remission vs 16 mm insole
452,453
Lequesne’s index of 1 RCT (N=66) urethane insole + 3 months and 3 months: -2.1
disease severity strapping + NSAID 6 months (urethane) and –
(change from baseline) vs rubber insole + (mid-study) 0.7 (rubber)
NSAID and at 2 years, 6 months: -2.2
end of study. (urethane) and –
0.9 (rubber)
2 years: -2.4
(urethane) and –
0.3 (rubber)
Urethane insole
better
453
Progression of Kellgren- 1 RCT (N=66) urethane insole + 2 years, end of NS
Lawrence Grade strapping + NSAID study
vs rubber insole +
NSAID
479
Tip pinch, kg (change 1 RCT (N=40) thumb strap splint 2 weeks (mid- NS
from baseline); Hand + abduction treatment)
function, Sollerman Test, exercises vs and at 6
ADL (change from control (short weeks (end of
baseline) opponens splint + treatment).
pinch exercises
485
Tip pinch strength, kg, 1 RCT (N=26) short opponens 1 week (end NS
(change from baseline) splint vs long of treatment)
at 1 week (end of opponens splint
treatment)
485
ADL, % same or easier at 1 RCT (N=26) short opponens 1 week (end Both groups
1 week (end of splint vs long of treatment) similar
treatment). opponens splint
Osteoarthritis

Knee
Insoles
50
Patient’s overall 1 MA , 1 RCT, laterally wedged 1 month, 3 NS
assessment N=147 insole vs neutrally months and 6
359
Patient’s global 1 RCT (N=156) laterally wedged 2 years (end NS
assessment (change insole vs neutrally of treatment)
from baseline) wedged insole
Taping
96
Patient’s preference 1 RCT (N=14) Medial taping vs 4 days (end of P<0.05
neutral taping treatment) Favours Medial
taping
96
Patient’s preference 1 RCT (N=14) Medial taping vs 4 days (end of NS
lateral taping treatment)

Knee
Brace
51
QoL measurements 1 RCT (N-=118) Knee brace + 3 months, 6 NS
(EuroQoL-5D) conservative months, 12
control overall
(conservative
treatment)
Taping
191
SF-36 bodily pain 1 RCT (N=87) Therapeutic tape 3 weeks end 3 weeks: +10.0
(change from baseline) vs control tape of treatment (therapeutic) and
and at 3 +5.5 (control)
weeks post- 3 weeks post-
treatment treatment: +7.9
(therapeutic) and
+2.0 (control)
Therapeutic tape
better
191
SF-36 physical function 1 RCT (N=87) Therapeutic tape 3 weeks end 3 weeks: +2.1
+2.0 (control)
Therapeutic tape
better
191
SF-36 physical role 1 RCT (N=87) Therapeutic tape 3 weeks end 3 weeks: +4.3
0.0 (control)
Osteoarthritis

Therapeutic tape
better
191
SF-36 physical function 1 RCT (N=87) Therapeutic tape 3 weeks post- +2.1 (therapeutic)
(change from baseline) vs control tape treatment and +4.4 (control)
Control tape
better
191
SF-36 physical role 1 RCT (N=87) Therapeutic tape 3 weeks post- +2.6 (therapeutic)
(change from baseline) vs control tape treatment and +13.0 (control)
Control tape
better
191
SF-36 bodily pain 1 RCT (N=87) Therapeutic tape 3 weeks end 3 weeks: +10.0
(change from baseline) vs no tape of treatment (therapeutic) and -
and at 3 3.7 (control)
(therapeutic) and -
2.0 (control)
Therapeutic tape
better
191
SF-36 physical function 1 RCT (N=87) Therapeutic tape 3 weeks end 3 weeks: +10.0
(change from baseline) vs no tape of treatment (therapeutic) and -
at 3 weeks end of and at 3 3.7 (control)
treatment (+2.1 and 0.0 weeks post- 3 weeks post-
respectively) and at 3 treatment treatment: +7.9
weeks post-treatment (therapeutic) and -
(+2.1 and –1.3 2.0 (control)
respectively); Therapeutic tape
better
191
SF-36 physical role 1 RCT (N=87) Therapeutic tape 3 weeks end 3 weeks: +4.3
(change from baseline) vs no tape of treatment (therapeutic) and
and at 3 +2.9 (control)
(therapeutic) and -
1.0 (control)
Therapeutic tape
better

Knee
Insoles
50
AEs (popliteal pain, low 1 MA , 1 RCT, subtalar strapped 8 weeks NS
back pain and foot sole N=90 insole vs inserted
pain). insole
Osteoarthritis

454
Number of AEs 1 RCT (N=62) 8 mm insole + 2 weeks (end P=0.003
strapping + NSAID of treatment) Favours 8 mm
vs 12 mm insole + insole
strapping + NSAID
454
Number of AEs 1 RCT (N=62) 12 mm insole + 2 weeks (end P=0.005
strapping + NSAID of treatment) Favours 12 mm
vs 16 mm insole + insole
strapping + NSAID
451
Total number of AEs 1 RCT (N=84) Urethane insoles + 4 weeks (end p=0.028
strapping + NSAID of treatment) Favours urethane
vs rubber insoles + insoles
strapping + NSAID
Taping
191
Number of patients 1 RCT (N=87) therapeutic tape 3 weeks (end 28% (therapeutic)
with AEs, skin irritation vs control tape of treatment) and 1% (control)
Control tape
better
191
Number of patients 1 RCT (N=87) therapeutic tape 3 weeks (end 28% (therapeutic
with AEs, skin irritation vs no tape of treatment) tape) and 0% (no
tape)
No tape better
Mixed
366
Number of patients 1 RCT (N=87) taping + exercises 10 weeks (end 16% (taping) and
with AEs (16% and 0% + posture of treatment) 0% (no
respectively). correction + intervention)
education vs No intervention
standard better
treatment (no
experimental
intervention)
Table 131: Analgesic use

Analgesic use outcome Reference Intervention time size
Knee
Insoles
50
Analgesic or NSAID use 1 MA , 1 RCT, laterally wedged Over 3 NS
N=147 insole vs neutrally months
wedged insole
19
Number of days 1 RCT (N=90) laterally wedged Over 6 weeks NS
receiving rescue insole vs neutrally (end of
medication wedged insole treatment)
359
NSAID usage, number of 1 RCT (N=156) laterally wedged Over 2 years 71 (lateral) and
days with NSAID intake insole vs neutrally (end of 168 (neutral),
wedged insole treatment) p=0.003
Favours lateral
Osteoarthritis

Analgesic use outcome Reference Intervention time size
wedge
359
Analgesic usage, number 1 RCT (N=156) laterally wedged Over 2 years NS
of days with analgesic insole vs neutrally (end of
intake; intra-articular wedged insole treatment)
Injection, mean number
of injections/patient.
Taping
191
Analgesic usage, 1 RCT (N=87) therapeutic tape Over 3 weeks NS
number of patients vs control tape (end of
treatment)
191
Analgesic usage, 1 RCT (N=87) therapeutic tape Over 3 weeks NS
number of patients. vs no tape (end of
treatment)
Mixed
452,453
Number of days with 1 RCT (N=66) urethane insole + over the 2 36.1% (urethane)
NSAID intake strapping + NSAID years and 42.2%
vs rubber insole + (rubber)
NSAID Urethane better
452,453
Number of patients 1 RCT (N=66) urethane insole + over the 6 N=1, 4.8%
who discontinued strapping + NSAID months (mid- (urethane) and
NSAIDs due to pain vs rubber insole + study N=2 (rubber) 9.5%
relief NSAID Urethane better
452,453
Number of patients 1 RCT (N=66) urethane insole + over the 6 N=1, 4.8%
who discontinued strapping + NSAID months (mid- (urethane) and
NSAIDs due to GI vs rubber insole + study N=2 (rubber) 9.5%
(stomach ache) AEs NSAID Urethane better
452,453
Number of patients 1 RCT (N=66) urethane insole + over the 6 3.4% (urethane)
who discontinued strapping + NSAID months (mid- and 3.1% (rubber)
NSAIDs due to AEs vs rubber insole + study
NSAID
Table 132: Withdrawals

Knee
Brace
51
Number of patients 1 RCT (N-=118) Knee brace + 3 months, 6 N=25 (brace) and
stopped treatment conservative months, 12 N=14
Number of patients treatment vs months or (conservative)
stopped treatment due to control overall Knee brace worse
strong reduction in (conservative
symptoms (N=3 and N=0 treatment)
respectively).
Osteoarthritis

51
Number of patients 1 RCT (N-=118) Knee brace + 3 months, 6 N=3 (brace) and
stopped treatment due to conservative months, 12 N=0 (conservative)
strong reduction in treatment vs months or Knee brace worse
symptoms control overall
(conservative
treatment)
51
Number of patients who 1 RCT (N-=118) Knee brace + 3 months, 6 N=15 (brace) and
stopped treatment due to conservative months, 12 N=14
lack of efficacy treatment vs months or (conservative)
control overall Knee brace worse
(conservative
treatment)
Insoles
50
Total number of 1 MA , 1 RCT, laterally wedged Not 33% (lateral) and
withdrawals N=147 insole vs neutrally mentioned 31% (neutral)
wedged insole Both groups
similar
Taping
191
Total number of 1 RCT (N=87) therapeutic tape 3 weeks post- Both: 0%
withdrawals vs control tape treatment Both groups same
191
Total number of 1 RCT (N=87) therapeutic tape 3 weeks post- 0% (therapeutic)
withdrawals vs no tape treatment and 3% (no tape)
Both groups
similar
Shoes
331
Total number of 1 RCT (N=125) Masai Barefoot 12 weeks (end 1.8% (MBT shoe)
withdrawals Technology (MBT) of treatment) and 1.5% (walking
Shoe vs high-end shoe)
walking shoe Both groups
similar
Mixed
366
Study withdrawals 1 RCT (N=87) taping + exercises 5 months (3 N=3, 7% (taping)
+ posture months post- and N=1, 2%
correction + treatment) (standard
education vs and at 12 treatment)
standard months (10 Both groups
treatment (no months post- similar
intervention)
452
Number of study 1 RCT (N=66) urethane insole + 3 months and NS
withdrawals strapping + NSAID 6 months
vs rubber insole + (mid-study)
NSAID for: and at 2 years
(end of study).
479
Total Withdrawals 1 RCT (N=40) thumb strap splint 6 weeks (end N=1, 5.2% (thumb
+ abduction of treatment) strap splint) and
exercises vs N=5, 24% (short
Osteoarthritis

control (short opponens splint)
opponens splint + Thumb splint
pinch exercises better
479
Withdrawals due to AEs 1 RCT (N=40) thumb strap splint 6 weeks (end N=1, 5.2% (thumb
+ abduction of treatment) strap splint) and
exercises vs N=1, 4.7% (short
control (short opponens splint)
opponens splint + Both groups
pinch exercises similar
Table 133: Structural changes

Structural changes Assessment Outcome / Effect
Knee
Insoles
359
JSW, mean narrowing 1 RCT (N=156) laterally wedged Rate/year NS
rate/year, mm. insole vs neutrally
wedged insole
8.6.4 Evidence statements: assistive devices
Table 134: Symptoms: pain

Hand osteoarthritis
430
Pain (VAS), % of patients 1 RCT (N=40) Assistive devices + 6 weeks, end 65% and 25%
improved exercise + of treatment respectively, p<0.05
education vs jar Favours assistive
opening aid + devices
education
Table 135: Symptoms: function

Hand osteoarthritis
430
Grip strength in both 1 RCT (N=40) Assistive devices + 6 weeks, end Both: p<0.05
hands (change from exercise + of treatment Favours assistive
baseline); Grip strength education vs jar devices
% of patients with 10% opening aid +
improvement in both education
hands
430
HAQ score 1 RCT (N=40) Assistive devices + 6 weeks, end NS
exercise + of treatment
education vs jar
opening aid +
education
Osteoarthritis
Table 136: Use of assistive devices

Use of devices outcome Reference Intervention time size
Hip or knee osteoarthritis
Use of assistive devices 1 observational Assistive devices n/a 59.3% of patients
472
(canes, crutches or study (N=27) used devices
walker)
Use of assistive devices 1 observational Assistive devices n/a 56% of patients used
440
study (N=88 devices and 27% of
participants patients used them
responses) often or very often
Site not specified

Total percentage of 1 observational Assistive devices n/a 67.3% (medical
436
patients using at least 1 study (N=248) devices) and 91.5%
assistive device (everyday devices)
Use of both medical and 1 observational Assistive devices n/a 59.7% (medical
436
everyday devices for study (N=248) devices) and 85.1%
personal care/in-home (everyday devices)
mobility
436
household activities and (everyday devices)
for community mobility
436
community mobility (everyday devices)
Number of assistive 1 observational Assistive devices n/a higher for patients

280
devices (all category study (N=66) with severe
types of device) needed osteoarthritis
by patients compared to
moderate arthritis
(number of devices =
94 and 36
respectively).
Table 137: Patient satisfaction / views of devices

Patient satisfaction / Assessment Outcome / Effect
views outcome Reference Intervention time size
Hip or knee osteoarthritis
Most effective 1 observational Assistive devices n/a 29.6% patients found
472
treatments out of study (N=27) assistive devices
different OIA therapies (canes crutches or
(assistive devices, cold, walker) were 1 of the
heat, rest, exercise and 3 most effective
joint protection) treatments
Use of canes 1 observational Assistive devices n/a perceived as useful
440
study (N=7 but some felt their
Osteoarthritis
Patient satisfaction / Assessment Outcome / Effect

views outcome Reference Intervention time size
participants) pride would be
affected and did not
use them
Coping strategies 1 observational Assistive devices n/a strategies included
440
study (N=7 the use of aids to
participants) daily living.
Helpfulness of aids and 1 observational Assistive devices n/a Rated moderately
440
adaptations study (N=88 and extremely
participants) helpful (29.5%);
rated not helpful or
slightly helpful (26%)
Site not specified

Positive attitudes 1 observational Assistive devices n/a Assistive devices
436
towards assistive study (N=248) helped people do
devices things they want to
do (94.8%), allowed
independence
(91.5%), were not
more bother than
they were worth
(94.0%)
Negative attitudes 1 observational Assistive devices n/a Devices were

436
towards assistive study (N=248) awkward (79%);
devices costs prevented use
(58.9%); devices
made people feel
dependent (48.4%)
Rate of satisfaction with 1 observational Assistive devices n/a Rate range: 78% to
280
assistive devices study (N=66) 100% (patients with
moderate and severe
arthritis). Lowest
satisfaction was with
vision devices.

There is a paucity of well designed trials in this area, and the GDG considered various additional
sources of evidence, including non-controlled studies. Evidence generally showed that aids and
devices are well accepted by many people with OA who report high satisfaction with use.
There are limited data for the effectiveness of insoles (either wedged or neutral) in reducing the
symptoms of knee OA. However in the absence of well-designed trial data and given the low cost of
the intervention, the GDG felt that attention to footware with shock-absorbing properties was worth
consideration.
There is some evidence for the effectiveness of walking aids and assistive devices (such as braces) for
hip and knee OA. Walking aids (ipsi- or contralateral cane use) can significantly improve stride length
and cadence.
Osteoarthritis
There is some evidence for the effectiveness of aids/ devices for hand OA. Thumb splints (of any
design) can help reduce pain from thumb OA and improve hand function. There are many different
designs of thumb CMC splint for OA described in the literature, frequently accompanied by
biomechanical rationales for which is most effective. As yet it is unclear which design/s are
considered most comfortable to patients, and thus will be worn long-term, and what degree of splint
rigidity/ support is required at what stage of OA in order to effectively improve pain and function.
The best study to date479 has included exercises within the trial design which confounds identifying
whether it was splinting or exercise which was most effective. Clinically, patients are commonly
provided with both a splint and exercise regime.
The role of Disability Equipment Assessment Centres was discussed. It was noted that the MDA
regularly publishes reports on assistive devices.
Referral: Hand osteoarthritis
This evidence suggests that those people with hand pain, difficulty and frustration with performing
daily activities and work tasks should be referred to occupational therapy for splinting, joint
protection training and assistive device provision. This may be combined with hand exercise training.
People should be referred early particularly if work abilities are affected.
Referral: Lower Limb
Provision of rehabilitation and physical therapies is commonly recommended in guidelines.

Physiotherapists and occupational therapists may be able to help with provision and fitting of
appropriate aids and devices. Insoles are commonly provided by podiatrists and orthotists but may
also be provided by physiotherapists and occupational therapists. Referral for, or direct local
provision of footwear advice should always be considered.
18.Offer advice on appropriate footwear (including shock-absorbing properties) as part of core

treatments (see recommendation 6) for people with lower limb osteoarthritis. [2008]
19.People with osteoarthritis who have biomechanical joint pain or instability should be
considered for assessment for bracing/joint supports/insoles as an adjunct to their core
treatments. [2008]
20.Assistive devices (for example, walking sticks and tap turners) should be considered as adjuncts
to core treatments for people with osteoarthritis who have specific problems with activities of
daily living. If needed, seek expert advice in this context (for example, from occupational
therapists or Disability Equipment Assessment Centres). [2008]
Osteoarthritis
8.7 Invasive treatments for knee osteoarthritis

In clinical practice arthroscopic lavage, debridement and tidal irrigation are invasive procedures
offered to patients who are failing medical management, predominantly for knee osteoarthritis.
There is no general consensus on which patients should be offered these procedures.
Arthroscopy usually involves a day-stay hospital admission with general anaesthesia and the
insertion of a fibre-optic instrument into the knee, allowing thorough inspection of pathology. The
joint is irrigated with a sizable volume of fluid, a process known as lavage, which may remove
microscopic and macroscopic debris resulting from cartilage breakdown, as well as removing the pro-
inflammatory effects of this material. This procedure may be associated with debridement, the
surgical “neatening” of obviously frayed cartilage or meniscal surfaces.
Tidal irrigation refers to the process of irrigating the joint and does not require general anaesthesia –
rather a needle is inserted in the knee under local anaesthesia and a large volume of fluid run into
the knee and then allowed to drain out. The rationale is the same as for arthroscopic lavage.
Evaluating these therapies is difficult due to the lack of standardised referral criteria, the absence of
many randomised trials and the lack of standardisation of co-therapies including exercises.

We looked for studies that investigated the efficacy and safety of arthroscopic lavage (with or
without debridement) compared with tidal irrigation and placebo (sham procedure) with respect to
symptoms, function, and quality of life in adults with osteoarthritis. Ten RCTs 318
44,66,99,162,202,212,231,302,373
were found on the outcomes of symptoms, function and quality of life, no
data for AEs was reported. No relevant cohort or case-control studies were found. Two RCTs202,302
were excluded as evidence due to methodological limitations.
The eight included RCTs were methodologically sound and were similar in terms of:
 Osteoarthritis site (all looked at knee osteoarthritis)
 Osteoarthritis diagnosis (radiologically)
 Trial design (parallel group).
However, they differed with respect to:

Table 138: Pain

Outcome / Effect
Pain outcome Reference Intervention Assessment time size
Knee
Lavage
318
KSPS (knee specific pain 1 RCT , N=180 Lavage vs 1 year or 2 years NS
scale, 0-100) placebo (sham post-intervention
Osteoarthritis
Outcome / Effect
procedure)
318
Arthritis Pain (0-100) 1 RCT , N=180 Lavage vs 2 weeks, 6 NS
placebo (sham weeks, 3 months,
procedure) 6 months, 1 year,
18 months and 2
years post-
intervention
318
KSPS (knee specific pain 1 RCT , N=180 Lavage + 1 year or 2 years NS
scale, 0-100) debridement vs post-intervention
placebo (sham
procedure)
318
Arthritis Pain (0-100) 1 RCT , N=180 Lavage + 2 weeks, 6 NS
debridement vs weeks, 3 months,
placebo (sham 6 months, 1 year,
procedure) 18 months and 2
years post-
intervention
66
AIMS Pain score; AIMS 1 RCT , N=34 Lavage + 3 months and 1 NS
Pain (Improvement of ≥ 1 debridement vs year post-
cm) tidal irrigation intervention
99
Pain at rest, VAS (change 1 RCT , N=20 Lavage vs 12 weeks post- -0.55 (lavage) and -
from baseline) control (saline intervention 2.1 (saline)
injection) Saline better
99
Pain walking, VAS 1 RCT , N=20 Lavage vs 12 weeks post- -2.85 (lavage) and -
(change from baseline) control (saline intervention 3.3 (saline)
99
Pain at night, VAS 1 RCT , N=20 Lavage vs 12 weeks post- -1.2 (lavage) and -5.0
(change from baseline) control (saline intervention (saline)
373
Pain (relative change) 1 RCT , N=98 Lavage vs 24 weeks post- p=0.02
placebo treatment Favours lavage
373
Clinical improvement in 1 RCT , N=98 Lavage vs 1 week, 4 weeks, 1 week: 48% (lavage)
Pain (% patients with at placebo 12 weeks and 24 and 25% (placebo)
least 30% pain reduction weeks post- 4 weeks: 48%
from baseline) at treatment (lavage) and 29%
(placebo)
12 weeks: 48%
(lavage) and 29%
(placebo)
24 weeks: 48%
(lavage) and 22%
(placebo).
Lavage better
Irrigation
44
WOMAC Pain (change 1 RCT , N=180 Tidal irrigation 12 weeks post- 21% (tidal) and 23%
from baseline, % of vs sham intervention (sham)
improvement irrigation Both groups similar
Osteoarthritis
Outcome / Effect
44
WOMAC Pain (change 1 RCT , N=180 Tidal irrigation 12 weeks, 24 12 weeks: -2.8 (tidal)
from baseline) vs sham weeks and 52 and -3.3 (sham)
irrigation weeks post- 24 weeks: -2.1 (tidal)
intervention and -2.7 (sham)
52 weeks -2.8 (tidal)
and -2.6 (sham)
44
Knee tenderness (change 1 RCT , N=180 Tidal irrigation 12 weeks, 24 12 weeks: -0.10
from baseline) vs sham weeks and 52 (tidal) and -0.17
irrigation weeks post- (sham)
intervention 24 weeks: -0.04
(tidal) and -0.07
(sham)
52 weeks -+0.06
(tidal) and -0.11
(sham)
212
Pain in the previous 24 1 RCT , N=77 Tidal irrigation Over 12 weeks p=0.02
hours (VAS) + medical Favours medical
management vs maagement
medical
management:
212
Pain after walking 50- 1 RCT , N=77 Tidal irrigation Over 12 weeks p=0.03
feet (VAS) + medical Favours medical
medical
management:
212
Pain after climbing 4 1 RCT , N=77 Tidal irrigation Over 12 weeks P<0.01
stairs (VAS) + medical Favours medical
medical
management:
231
Pain, VAS (change from 1 RCT , N=90 Full irrigation vs 12 weeks post- Favours full irrigation
baseline) minimal intervention
irrigation
231
Pain, VAS (change from 1 RCT , N=90 Full irrigation vs 12 weeks post- 1.47, 95% CI –1.2 to
baseline - analysis of minimal intervention 4.1 (full) and 0.12,
covariance with irrigation irrigation 95%CI 0 to 0.3
group as independent (minimal); p=0.02
variable, baseline score Favours full irrigation
and swelling as
covariates)
231
WOMAC pain (change 1 RCT , N=90 Full irrigation vs 12 weeks post- 4.2, 95% CI –0.9 to
from baseline - analysis minimal intervention 9.4 (full) and 2.3, 95%
of covariance with irrigation CI –0.1 to 4.7
irrigation group as (minimal); p=0.04
independent variable, Favours full irrigation
baseline score and
swelling as covariates)
231
WOMAC pain (change 1 RCT , N=90 Full irrigation vs 12 weeks post- NS
Osteoarthritis
Outcome / Effect
from baseline) minimal intervention
irrigation
Table 139: Stiffness

Knee
Lavage
99
Immobility stiffness, 1 RCT , N=20 Lavage vs control 12 weeks -9.5 (lavage) and
mins (change from (saline injection) post- +7.5 (placebo)
baseline) intervention Lavage better
99
Morning stiffness, 1 RCT , N=20 Lavage vs control 12 weeks -6.0 (lavage) and -
mins (change from (saline injection) post- 3.8 (saline)
baseline) intervention Saline better
Irrigation
44
WOMAC stiffness 1 RCT , N=180 Tidal irrigation vs 12 weeks, 24 12 weeks: -0.7
(change from baseline) sham irrigation weeks and 52 (tidal) and -1.2
weeks post- (sham)
intervention. 24 weeks: -0.6
(tidal) and -0.9
(sham)
52 weeks: -0.7
(tidal) and -0.9
(sham)
Both groups similar
212
Knee stiffness, number 1 RCT , N=77 Tidal irrigation + 12 weeks P=0.03
of days/week medical post- Favours tidal
management vs intervention
medical
management:
212
Stiffness with 1 RCT , N=77 Tidal irrigation + 12 weeks p=0.01
inactivity medical post- Favours tidal
management vs intervention
medical
management:
231
WOMAC stiffness 1 RCT , N=90 Full irrigation vs 12 weeks NS
(change from minimal irrigation post-
baseline); WOMAC intervention
stiffness (change from
baseline - analysis of
covariance with
irrigation group as
independent variable,
baseline score and
swelling as covariates)
Osteoarthritis
Table 140: Function

Outcome / Effect
Function outcome Reference Intervention Assessment time size
Knee
Lavage
318
Self-reported ability to 1 RCT , N=180 Lavage vs placebo 1 year or 2 years NS
walk and bend (AIMS2- (sham procedure) post-intervention
WB score)
318
Physical functioning 1 RCT , N=180 Lavage vs placebo 2 weeks, 6 NS
scale (30-m walk time (sham procedure) weeks, 3 months,
and stair climb time, 6 months, 1 year,
mins) 18 months and 2
years post-
intervention
318
Physical functioning 1 RCT , N=180 Lavage + 1 year or 2 years 2 weeks: 56.0
scale (30-m walk time debridement vs post-intervention (lavage) and 48.3
and stair climb time, placebo (sham (sham); p=0.02
secs) procedure) 1 year 52.5
(lavage) and 45.6
(sham); p=0.04
Favours sham
318
Self-reported ability to 1 RCT , N=180 Lavage + 1 year or 2 years NS
walk and bend (AIMS2- debridement vs post-intervention
WB score) placebo (sham
procedure)
318
Physical functioning 1 RCT , N=180 Lavage + 2 weeks, 6 NS
scale (30-m walk time debridement vs weeks, 3 months,
and stair climb time, placebo (sham 6 months, 1 year,
secs) procedure) 18 months and 2
years post-
intervention
66
AIMS Physical activity; 1 RCT , N=34 Lavage + 3 months and 1 NS
AIMS Physical function; debridement vs year post-
Active range of motion tidal irrigation intervention
(degrees); 50-foot walk
time (secs)
99
25 yard walk time, secs 1 RCT , N=20 Lavage vs control 12 weeks post- -23.0 (lavage) and
(change from baseline) (saline injection) intervention -6.0 (saline)
Saline better
99
Knee flexion, degrees 1 RCT , N=20 Lavage vs control 12 weeks post- +4.0 (lavage) and
(change from baseline) (saline injection) intervention +9.0 (saline)
Saline better
373
Lequesne’s functional 1 RCT , N=98 Lavage vs placebo 24 weeks post- NS
index treatment
Irrigation
44
WOMAC Physical 1 RCT , N=180 Tidal irrigation vs 12 weeks post- 17% (tidal) and
functioning (change sham irrigation intervention 21% (sham)
from baseline) Both groups
similar
Osteoarthritis
Outcome / Effect
Function outcome Reference Intervention Assessment time size
44
WOMAC function 1 RCT , N=180 Tidal irrigation vs 12 weeks, 24 12 weeks: -7.7
(change from baseline sham irrigation weeks and 52 (tidal) and -10.8
weeks post- (sham)
(tidal) and -8.7
(sham)
52 weeks -7.7
(tidal) and -9.6
(sham)
44
50-foot walk time 1 RCT , N=180 Tidal irrigation vs 12 weeks, 24 12 weeks: -0.4
(change from baseline) sham irrigation weeks and 52 (tidal) and -0.6
weeks post- (sham)
(tidal) and -0.7
(sham)
52 weeks -0.5
(tidal) and -0.4
(sham)
212
50-foot walk time; 4- 1 RCT , N=77 Tidal irrigation + Over 12 weeks NS
stair climb time; Passive medical
and active range of management vs
motion. medical
management:
231
WOMAC total (change 1 RCT , N=90 Full irrigation vs 12 weeks post- NS
from baseline); WOMAC minimal irrigation intervention
total (change from
baseline - analysis of
covariance with
irrigation group as
baseline score and
swelling as covariates);
WOMAC function
(change from baseline);
WOMAC function
(change from baseline -
analysis of covariance
with irrigation group as
baseline score and
swelling as covariates).
Table 141: Global Assessment

Knee
Lavage
66
Physicians global 1 RCT , N=34 Lavage + 1 year post- 41% (lavage) and
assessment (% debridement vs intervention 23% (tidal), p<0.05
improved) tidal irrigation Favours lavage
Osteoarthritis

66
Physicians global 1 RCT , N=34 Lavage + 3 months NS
assessment (% debridement vs post-
improved) tidal irrigation intervention
66
Patients global 1 RCT , N=34 Lavage + 3 months and NS
assessment (VAS); debridement vs 1 year post-
Patients global tidal irrigation intervention
assessment
(Improvement of ≥ 1
cm)
373
Global status 1 RCT , N=98 Lavage vs placebo 24 weeks NS
post-
treatment
Irrigation
44
Physician’s assessment 1 RCT , N=180 Tidal irrigation vs 12 weeks, 24 12 weeks: -8 (tidal)
of arthritis global sham irrigation weeks and 52 and -9 (sham)
activity (number of weeks post- 24 weeks: -9 (tidal)
patients ‘severe’, intervention and -13 (sham)
change from baseline) 52 weeks -9 (tidal)
and -13 (sham)
44
Physician’s assessment 1 RCT , N=180 Tidal irrigation vs 12 weeks, 24 12 weeks: -+19
of arthritis global sham irrigation weeks and 52 (tidal) and +29
activity (number of weeks post- (sham)
patients ‘mild’, change intervention 24 weeks: +15
from baseline) at 12 (tidal) and +19
weeks post- (sham)
intervention (+19 and 52 weeks +15
+29 respectively), at 24 (tidal) and +21.4
weeks post- (sham)
intervention (+15 and
+19 respectively) and at
52 weeks post-
intervention (+15 and
+21 respectively);
212
Patients assessment of 1 RCT , N=77 Tidal irrigation + Over 12 weeks p<0.01 at all time
treatment efficacy medical periods
management vs Favours tidal
medical
management:
212
Patients assessment of 1 RCT , N=77 Tidal irrigation + Over 12 weeks N=17/29 (tidal) and
treatment as medical N=11/28 (medical)
somewhat or very management vs Favours tidal
effective at relieving medical
pain management:
212
Physician’s assessment 1 RCT , N=77 Tidal irrigation + Over 12 weeks P=0.02 at all time
of treatment as medical periods
somewhat or very management vs Favours tidal
effective at relieving medical
pain. management:
Osteoarthritis


Knee
Lavage
66
AIMS social activity 1 RCT , N=34 Lavage + 3 months and NS
score; AIMS depression debridement vs 1 year post-
score; tidal irrigation intervention
AIMS anxiety score
Irrigation
44
QWB score (change 1 RCT , N=180 Tidal irrigation vs 24 weeks and Both: 0.02 (tidal)
from baseline) sham irrigation 52 weeks and 0.0 (sham)
post- Both groups similar
intervention
Table 143: Use of rescue medication / analgesia

Rescue medication Assessment Outcome / Effect
Knee
Irrigation
44
Use of medication 1 RCT , N=180 Tidal irrigation vs 12 weeks N=18 (tidal) and
(NSAIDs, narcotic sham irrigation post- N=32 (sham)
analgesia, muscle intervention Tidal better
relaxants,
antidepressants,
glucosamine or
chondroitin sulphate)
44
Use of medication 1 RCT , N=180 Tidal irrigation vs 24 weeks and 24 weeks: both
(NSAIDs, narcotic sham irrigation 52 weeks N=29
analgesia, muscle post- 52 weeks: N=36
relaxants, intervention (tidal) and N=32
antidepressants, (sham)
glucosamine or Both groups similar
chondroitin sulphate)
44
Paracetamol use 1 RCT , N=180 Tidal irrigation vs 12 weeks, 24 12 weeks: +1.1
(change from baseline, sham irrigation weeks and 52 (tidal) and +0.1
mean number of weeks post- (sham)
tablets/day) intervention 24 weeks: +1.4
(tidal) and +0.6
(sham)
52 weeks: +0.8
(tidal) and +0.1
(sham)
Both groups similar
Osteoarthritis
Table 144: Other

Assessmen
Other outcome Reference Intervention t time Outcome / Effect size
Knee
Irrigation
162
The Clinical scores for 1 RCT , N=20 Lavage vs Lavage + 6 and 12 6 weeks: 33.7 (lavage) and
symptoms and debridement weeks 32.7 (lavage +
mobility post- debridement)
interventio 12 weeks: 33.9 (lavage)
n and 33.0 (lavage +
debridement)
No improvement in either
group

Arthroscopic lavage and debridement are surgical procedures that have become widely used. Tidal
irrigation, through large bore needles, has been practiced by physicians to a limited degree. These
procedures have limited risks, though arthroscopy usually involves a general anaesthetic. These
procedures are offered to patients when usual medical care is failing or has failed and the next
option, knee arthroplasty, appears too severe, for a variety of reasons, for either the patient or the
medical advisor.
Arthroscopy may be indicated for true locking, caused by meniscal lesions or loose bodies in the knee
joint. These situations are uncommon in patients with osteoarthritis of the knee.
Many procedures in medicine have a large placebo effect and when assessing minimalistic surgical
procedures it can be very difficult to separate this placebo effect from the surgical procedure itself.
21.Do not refer for arthroscopic lavage and debridementg as part of treatment for osteoarthritis,
unless the person has knee osteoarthritis with a clear history of mechanical locking (as opposed
to morning joint stiffness, 'giving way' or X-ray evidence of loose bodies). [2008, amended 2014]
g
This recommendation is a refinement of the indication in Arthroscopic knee washout, with or without debridement, for
the treatment of osteoarthritis (NICE interventional procedure guidance 230). The clinical and cost-effectiveness evidence
for this procedure was reviewed for the original guideline (published in 2008), which led to this more specific
recommendation on the indication for which arthroscopic lavage and debridement is judged to be clinically and cost
effective.
Osteoarthritis
Pharmacological management of osteoarthritis
9 Pharmacological management of osteoarthritis

9.1 Introduction
This update originally intended to make recommendations following the review of new evidence in
relation to the use of paracetamol in the management of OA because of concerns linked to its
efficacy and safety. New evidence was also to be considered in relation to etoricoxib and the use of
fixed dose combinations of NSAIDs and gastroprotective agents.
Update 2014
Recommendations made following the review of evidence in these areas were presented at the
consultation stage of this guideline. Stakeholder feedback at consultation indicated that the
recommendations made, particularly in relation to paracetamol, were of limited clinical application
without a full review of the pharmacological management of OA. The MHRA are currently conducting
work around the over-the counter-availability of NSAIDs and Paracetamol alongside a review of the
safety of these medications. NICE intends to commission a full update of the pharmacological
management of OA following publication of that work. In the interim period, the recommendations
from the original guideline remain current advice and the original evidence is presented below.
The GDG however do wish to draw attention to the findings of the review of the effectiveness of
paracetamol presented in the consultation version of the guideline. This review reached some
important conclusions regarding its use in the management of osteoarthritis that the GDG believe
should be used to guide prescribing practice in this interim period.
Appropriate pharmacological analgesia forms one of the key platforms for treating osteoarthritis
when non-pharmacological therapy on its own is insufficient. The use of such analgesia may be
aimed at different aspects of a person’s pain, including night pain or exercise-associated pain. Oral
analgesics, especially paracetamol, have been used for many years, with increasing use of opioid
analgesics in recent years, partly fuelled by fears over the safety of NSAIDs. The exact mechanism of
action of paracetamol is unclear, although it may work in part by inhibiting prostaglandin synthesis;
its action seems to work via the central nervous system rather than through peripheral effects.
Opioid analgesics work by action on endogenous opioid receptors in the central nervous system.
There is still surprisingly little data on how people with OA use these therapies, which may influence
their efficacy (for example, intermittent usage only at times of increased pain versus regular daily
dosing). There are also many assumptions made on the effectiveness of these therapies in
osteoarthritis, based on concepts such as ‘analgesic ‘ladders’ which are not well supported in
osteoarthritis cohorts.
It should be noted that this chapter includes the use of tricyclic agents as analgesics in osteoarthritis.
This refers to the concept of low-dose usage of these agents, rather than anti-depressant doses; it
has been suggested that such low dose usage may result in significant anti-nociceptive effects.
However it is important to note that depression may be associated with any chronic painful condition
such as osteoarthritis and may require treatment in its own right. Readers should refer to the NICE
depression guidelines.
9.1.1 Methodological introduction: paracetamol versus NSAIDs including COX-2 inhibitors

We looked at studies on the efficacy and safety of paracetamol compared with oral NSAIDs or
selective COX-2 inhibitors for symptomatic relief from pain in adults with osteoarthritis. We found
one Cochrane meta-analysis 457,458 of randomised controlled trials that addressed the topic. In
addition, one RCT444,444our relevant n of 1 trials 281,332,483,504and one cohort study155 were identified. All
studies were found to be methodologically sound and were included as evidence.
Osteoarthritis
The meta-analysis included ten RCTs with comparisons between paracetamol and NSAIDs (ibuprofen,
diclofenac, arthrotec, celecoxib, naproxen, and rofecoxib). The analysis did not provide separate
results for non-selective and COX-2 selective NSAIDs on pain outcomes, but did for gastro-intestinal
adverse events. Studies included in the analysis differed with respect to:
 Paracetamol dosage
 Site of disease
 Osteoarthritis diagnosis
 Trial design
 Funding sources
 Study site location
To avoid double counting of participants receiving paracetamol, the analysis was stratified into three
comparator groups involving paracetamol and:
 Ibuprofen 2400 mg, diclofenac, arthrotec, celecoxib, naproxen (comparator 1)
 Ibuprofen 1200 mg, arthrotec, rofecoxib 25 mg, naproxen (comparator 2)
 ibuprofen 1200 mg, arthrotec, rofecoxib 12.5 mg, naproxen (comparator 3)
The four n of 1 trials reported on courses of paracetamol and NSAIDs given in random order to
blinded participants acting as their own controls. There were high numbers of non-completers across
all studies. One cohort study retrospectively examined the prevalence of serious gastro-intestinal
adverse events in participants taking paracetamol or Ibuprofen.
The RCT444,444 looked at paracetamol (4g per day) versus naproxen (750 mg per day) in n=581 patients
with knee or hip osteoarthritis in a 12-month or 6-month treatment phase.
9.1.2 Methodological introduction: paracetamol versus opioids, and paracetamol-opioid

combinations
We looked at studies that investigated the efficacy and safety of i) paracetamol compared with
opioids or opioid-paracetamol compounds, and ii) NSAIDs compared with opioid-paracetamol
compounds to relieve pain in adult patients with osteoarthritis. One Cochrane systematic review and
meta-analysis 60,60, six RCTs 34,42,214,243,297,341 and one prospective cohort study 315 were found on
paracetamol versus opioids, paracetamol versus paracetamol-opioids, NSAIDs versus paracetamol-
opioids and opioids versus NSAIDs. The cohort study had a mixed arthritis population, did not stratify
the study findings in terms of diagnostic category, and had multiple methodological limitations. This
study was therefore excluded.
The Cochrane meta-analysis only included one RCT comparing the opioid tramadol (up to 300 mg per
day) to the NSAID diclofenac (up to 150 mg perday) for 28 days of treatment in n=108 patients with
hip or knee osteoarthritis. The RCT was assessed for quality and found to be methodologically sound.
The number of included RCTs addressing individual questions were as follows:

 paracetamol versus opioids 34,42,243
 paracetamol-opioid combinations 214,297,341
Studies differed with respect to the anatomical site of osteoarthritis, and treatment regimens (doses
and treatment length). All studies included as evidence had methodological issues, including:
 Small sample sizes
 inadequate blinding
Osteoarthritis
 no washout period for previous analgesic medication

 ITT analysis rarely performed.
9.1.3 Methodological introduction: opioids

We looked at studies that investigated the efficacy and safety of low-dose opioids with or without
paracetamol compared with higher-strength opioids with respect to symptoms, function, and quality
of life in adults with osteoarthritis. Two systematic reviews and meta-analyses 38,60 and four RCTs 219
37 10,158
were found that addressed the question. One RCT 10 was excluded due to methodological
limitations.
The Cochrane systematic review 60,60 included three RCTs (n=467 patients) comparing tramadol
(opioid) with placebo and 2 RCTs (N=615 patients) comparing tramadol (opioid)-paracetamol with
placebo comparing tramadol (opioid) with NSAID (diclofenac).
Opioid versus placebo
The three RCTs included in the meta-analysis were similar in terms of trial design (parallel-group
studies), blinding (double blind) and study quality. However, trials varied in terms of:
 osteoarthritis site (two RCTs knee, one RCT hip or knee)
 treatment regimen – dose of tramadol one RCT 200mg per day, two RCTs up to 400mg per day)
Opioid-paracetamol combinations versus placebo
The two RCTs included in the meta-analysis were similar in terms of trial design (parallel-group
studies), blinding (double blind) and study quality. However, trials varied in terms of:
 Dose of tramadol 37.5 mg per day, paracetamol 325 mg perday (increased to 4 or 8 tablets per
day further into the trial).
The second systematic review 38,38 included 63 RCTs (of which N=6 RCTs compared opioids with
placebo, N=1057 patients) and assessed the outcome of pain. Trials were similar in terms of
osteoarthritis site (knee osteoarthritis) and study quality. However, trials varied in terms of:
 Treatment – type of opioid used (n=2 RCTs tramadol, n=2 RCTs oxymorphone, n=1 RCT
oxycodone, n=1 RCT codeine, n=1 RCT morphine sulphate).
NOTE: The Bjordal et al meta-analysis38,38 includes 2 RCTs that were also included in the Cepeda et al
meta-analysis60,60 however both meta-analyses included a number of different additional studies and
thus both meta-analyses were included as evidence.
The three included RCTs were methodologically sound and assessed patients with knee and/or hip
osteoarthritis. The first RCT37 was a cross-over study and compared low dose tramadol with
pentazocine in n=40 patients for a 2-week treatment period. The second RCT 219 was parallel group
design compared dextropropoxyphene with high dose tramadol in n=264 patients for a 2-week
treatment period. The third RCT158 compared tramadol (at increasing doses 100, 200, 300 and 400
mg /day) with placebo for a 12-week treatment period.
The cross-over study37 did not include a wash-out period between treatment periods, however in an
attempt to reduce the influence of any carry-over effects, the final 7 days of each treatment period
Osteoarthritis
were used to compare the treatments. This study also had a high withdrawal rate (48%), but was
otherwise fairly well conducted. The parallel group study 219 was methodologically sound.
9.1.4 Methodological introduction: paracetamol vs placebo

We looked at studies that investigated the efficacy and safety of paracetamol compared to placebo
with respect to symptoms, function, and quality of life in adults with osteoarthritis. We found one
Cochrane systematic review and meta-analysis 459 and 2 RCTs 7,185 on paracetamol versus placebo.
The Cochrane meta-analysis assessed the RCTs for quality and pooled together all data for the
outcomes of symptoms, function and AEs. However, the outcomes of quality of life and GI AEs were
not reported. The results for these outcomes have been taken from the individual RCTs included in
the systematic review. No relevant RCTs, cohort or case-control studies were found.
Outcomes in the RCTs of the MA were analysed by a number of different assessment tools, using
either categorical or quantitative data. For continuous outcome data, the MA has used SMD
(standardised mean difference) to pool across RCTs. For dichotomous outcome data, the MA has
calculated RR.
The meta-analysis included 7 RCTs (with N=2491 participants) that focused on comparisons between
paracetamol and placebo. Studies included in the analysis differed with respect to:
 Paracetamol dosage (5 RCTs 1000mg daily, 2 RCTs 4000 mg daily)

 Site of disease (5 RCTs knee, 2 RCTs knee or hip)
 Osteoarthritis diagnosis (5 RCTs radiological, 1 RCT clinical and radiological, 1 RCT Lequesne
criteria)
 Trial length and design (4 RCTs were parallel group design, 3 RCTs cross-over design)
 Funding sources (3 RCTs had involvement of a pharmaceutical company)
The 2 RCTs7,185 not included in the systematic review were parallel studies that focused on the
outcomes of symptoms, function and AEs. The first RCT (Altman et al.) 7 was methodologically sound
(randomised and double-blind) and compared paracetamol ER (3900 mg/day) versus paracetamol ER
(1950 mg/day) versus placebo in N=483 patients with knee or hip osteoarthritis in a 12 week
treatment phase. The second RCT (Beaumont et al.)185 was methodologically sound (randomised and
double-blind) and compared paracetamol ER (3000 mg/day) versus placebo or glucosamine sulphate
in N=325 patients with knee osteoarthritis in a 6 months treatment phase. The results for the
glucosamine arm are not presented here.
9.1.5 Methodological introduction: tricyclics, SSRIs and SNRIs

We looked for studies that investigated the efficacy and safety of tricyclics/SSRI/SNRI drugs
compared with placebo with respect to symptoms, function, and quality of life in adults with
osteoarthritis. One RCT412 was found that on the outcomes of symptoms and function. No relevant
cohort or case-control studies were found.
The RCT412 (n=24) was a cross-over design involving a mixed population of osteoarthritis (n=7),
rheumatoid arthritis (n=14) or ankylosing spondylitis (n=1) patients who were randomised to
treatment with the tricyclic antidepressant Imipramine or placebo. Results for osteoarthritis patients
only are reported here. The study length was 6 weeks (3 weeks for each treatment). The results for
each patient were reported separately and therefore the osteoarthritis data has been extracted. The
Osteoarthritis
anatomical site of osteoarthritis was not mentioned and adverse events were not reported for the
separate osteoarthritis subgroup. Overall, the study was fairly well conducted (although it did not
include a wash-out period between treatments) and is therefore included as evidence.
9.1.6 Evidence statements: paracetamol versus NSAIDs including COX-2 inhibitors

Assessment
457,458
Rest pain 1 MA ,3 NSAIDs (ibuprofen Mean SMD –0.20, 95% CI–0.36
RCTs 2400 mg, diclofenac, duration 13.1 to –0.03, p<0.05
arthrotec, celecoxib, weeks (range Favours NSAIDs
naproxen) versus 1-104 weeks)
paracetamol
457,458
Rest pain 1 MA ,4 NSAIDs (ibuprofen Mean SMD –0.19, 95% CI –0.35
RCTs 1200 mg, arthrotec, duration 13.1 to –0.03, p<0.05
rofecoxib 25 mg, weeks (range Favours NSAIDs
paracetamol
457,458
Overall pain 1 MA ,8 NSAIDs (ibuprofen Mean SMD –0.25, 95% CI –0.33
paracetamol
457,458
Overall pain 1 MA ,7 NSAIDs (ibuprofen Mean SMD –0.31, 95% CI –0.40
paracetamol
457,458
Pain on motion 1 MA NSAIDs versus Mean NS
paracetamol duration 13.1
weeks (range
1-104 weeks)
457,458
WOMAC pain 1 MA ,2 NSAIDs (ibuprofen Mean SMD –0.24, 95% CI –0.38
paracetamol
457,458
WOMAC pain 1 MA ,2 NSAIDs (ibuprofen Mean SMD –0.37, 95% CI –0.50
paracetamol
457,458
WOMAC pain 1 MA ,1 NSAIDs (ibuprofen Mean SMD – 0.31, 95% CI –0.48
RCT 1200 mg, arthrotec, duration 13.1 to –0.13, p<0.05
rofecoxib 12.5 mg, weeks (range Favours NSAIDs
paracetamol
457,458
Lequesne pain 1 MA NSAIDs versus Mean NS
weeks (range
1-104 weeks)
Osteoarthritis
Assessment
281
Symptom control 1 N of 1 trial NSAIDs versus n/a NS (53% of patients), 33%
/ pain relief (N=25) paracetamol preferred NSAIDs
Pain relief 1 N of 1 trial NSAIDs versus n/a 20% preferred NSAIDs,

332,332
(N=116) paracetamol 4% preferred paracetamol
NSAIDs better
Pain (VAS), 1 N of 1 Celecoxib versus n/a Effect size 0.2.
504,504
differences in study (N=5 paracetamol Celecoxib better
mean scores 9)
Overall symptom 1 N of 1 Celecoxib versus n/a NS for 80% of patients

504,504
relief study (N=5 paracetamol Remaining patients -
9) Celecoxib better
444,444
WOMAC pain 1 RCT Naproxen versus 6 months NS
(N=581) paracetamol (end of
treatment)
Table 146: Symptoms: stiffness

Stiffness Assessment
outcome Reference Intervention time Outcome / Effect size
457,458
WOMAC stiffness 1 MA ,3 NSAIDs (ibuprofen Mean SMD –0.20, 95% CI –0.34
paracetamol
457,458
WOMAC stiffness 1 MA ,4 NSAIDs (ibuprofen Mean Significant heterogeneity
RCTs 1200 mg, arthrotec, duration 13.1
rofecoxib 25 mg, weeks (range
paracetamol
457,458
WOMAC stiffness 1 MA ,8 NSAIDs (ibuprofen Mean SMD –0.26, CI 95% –0.43
rofecoxib 12.5 mg, weeks (range Favours NSAIDs
paracetamol
stiffness relief 1 n of 1 trial NSAIDs versus n/a More patients (13%)
332,332
(patients (n=116) paracetamol preferred NSAIDs to
preference) paracetamol although for
most there was no clear
preference between the
two treatments. 2%
preferred paracetamol.
Stiffness (VAS), 1 n of 1 Celecoxib versus n/a Effect size 0.3.
504,504
differences in study (n=5 paracetamol Celecoxib better
mean scores 9)
444,444
WOMAC stiffness 1 RCT Naproxen versus 6 months Both groups similar.
Osteoarthritis
Stiffness Assessment
(n=581) paracetamol (end of
treatment)
Table 147: Symptoms: Function

Function Assessment
Function 1 n of 1 Celecoxib versus n/a Effect size 0.3.
504,504
(patient-specific study (n=5 paracetamol Celecoxib better
functional scale), 9)
differences in
mean scores
functional 1 n of 1 Celecoxib versus n/a 2/42 completers
504,504
limitation study (n=5 paracetamol celecoxib better
9)
444,444
WOMAC function 1 RCT Naproxen versus 6 months Both groups similar.
(n=581) paracetamol (end of
treatment)
Table 148: Global efficacy

Global efficacy Assessment
457,458
WOMAC total 1 MA ,3 NSAIDs (ibuprofen Mean SMD –0.25, 95% CI–0.39
paracetamol
457,458
WOMAC total 1 MA ,1 NSAIDs (ibuprofen Mean SMD –0.46, 95% CI -0.73
RCT 1200 mg, arthrotec, duration 13.1 to –0.19, p<0.05
paracetamol
457,458
Patient global 1 MA ,2 NSAIDs (ibuprofen Mean NS
assessment of RCTs 2400 mg, diclofenac, duration 13.1
overall efficacy arthrotec, celecoxib, weeks (range
paracetamol
457,458
Patient global 1 MA ,2 NSAIDs (ibuprofen Mean RR 1.23, 95% CI 1.06 to
assessment of RCTs 2400 mg, diclofenac, duration 13.1 1.43, p<0.05
overall efficacy arthrotec, celecoxib, weeks (range Favours NSAIDs
paracetamol
457,458
Patient global 1 MA ,3 NSAIDs (ibuprofen Mean RR 1.50, 95% CI 1.27 to
assessment of RCTs 1200 mg, arthrotec, duration 13.1 1.76, p<0.05
overall efficacy rofecoxib 25 mg, weeks (range Favours NSAIDs
paracetamol
457,458
Patient global 1 MA ,3 NSAIDs (ibuprofen Mean Significant heterogeneity
assessment of RCTs 1200 mg, arthrotec, duration 13.1
overall efficacy rofecoxib 12.5 mg, weeks (range
Osteoarthritis
Global efficacy Assessment

paracetamol
457,458
Physician global 1 MA NSAIDs versus Mean NS
assessment of paracetamol duration 13.1
overall efficacy weeks (range
1-104 weeks)
332,332
Patient 1 RCT , NSAIDs versus n/a 5% favoured NSAIDs, and
preference (for n=116 paracetamol 2% favoured paracetamol
pain and Both groups similar
stiffness)
Patient 1 n of 1 NSAIDs versus n/a 71% = no preference
483,483
preference (for trial , n=13 paracetamol participants
general efficacy) 29% = preferred NSAIDs
Table 149: General Adverse Events (AEs)

AEs Assessment
457,458
total number of 1 MA NSAIDs versus Mean NS
patients with AEs paracetamol duration 13.1
weeks (range
1-104 weeks)
frequency of AEs 1 n of 1 trial NSAIDs versus n/a NS
(March et al. paracetamol
1041-45), n=25
frequency of AEs 1 N of 1 NSAIDs versus n/a NS
483,483
trial , n=13 paracetamol
Number of AEs 1 N of 1 trial NSAIDs versus n/a 41% = more AEs with
332,332
, n=116 paracetamol NSAIDs and 31% same in
both groups and 28% =
more AEs with
paracetamol
NSAIDs worse
Number of 1 N of 1 Celecoxib versus SR n/a N=5 – celecoxib worse
504,504
patients with AEs study (n=5 paracetamol N=9 – pracetamol worse
9) N=25 – NS difference
Both groups similar
444,444
number of 1 RCT Naproxen versus 6 months NS
patients with ≥1 (n=581) paracetamol (end of
AE treatment)
444,444
number of 1 RCT NSAIDs versus 6 months 3.5% (naproxen) and 2.5%
patients with (n=581) paracetamol (end of (paracetamol)
SAEs treatment) Both groups similar
Osteoarthritis
Table 150: Gastro-intestinal adverse events (AEs)

GI AEs Assessment
Outcome Reference Intervention time Outcome / Effect size
457,458
Number of GI AEs 1 MA ,5 Non-selective NSAIDs Mean Significant heterogeneity
RCTs vserus paracetamol duration 13.1 RR 1.47, 95% CI 1.08 to
weeks (range 2.00, p<0.05.
1-104 weeks) Favours paracetamol
457,458
Number of GI AEs 1 MA NSAIDs versus Mean NS
weeks (range
1-104 weeks)
457,458
Number of GI AEs 1 MA COX-2 versus Mean NS
weeks (range
1-104 weeks)
Number of 1 cohort Ibuprofen versus Not 0.2% (paracetamol) and
155
patients with study n=3124 paracetamol mentioned 0.3% (ibuprofen)
initial GI AEs Both groups similar
GI AE rates per 1 cohort Ibuprofen versus Not Rates: 2.1 (paracetamol)

155
1000 patient study n=3124 paracetamol mentioned and 2.4 (ibuprofen)
years Both groups similar
GI AE rates per 1 cohort Ibuprofen versus Not 101-1100 mg rates: 0
155
1000 patient study n=3124 paracetamol (Both mentioned (paracetamol) and 3.2
years drugs at doses of 101- (ibuprofen) = Ibuprofen
1100 mg, >2000mg and worse
at 1301-2600 mg) >2000 mg rates: 0
(paracetamol) and 9.1
(ibuprofen) = Ibuprofen
worse
1301-2600 mg rates: 8.97
(paracetamol) and 0
(ibuprofen) = paracetamol
worse
Number of 1 n of 1 Celecoxib versus SR n/a Stomach pain: 27%

504,504
patients with study (n=5 paracetamol (paracetamol) and 15%
Stomach pain 9) (celecoxib)
and vomiting Vomiting: 7%
(paracetamol) and 2%
(celecoxib)
Celecoxib better
444,444
Number of GI AEs 1 RCT NSAIDs versus 6 months Constipation: p<0.002
(constipation and (n=581) paracetamol (end of Peripheral oedema:
peripheral treatment) p<0.033
oedema) Favours paracetamol
Osteoarthritis

Withdrawals Assessment
457,458
Total number of 1 MA ,5 Non-selective NSAIDs Mean NS
withdrawals due RCTs vs paracetamol duration 13.1
to AEs weeks (range
1-104 weeks)
457,458
Total number of 1 MA NSAIDs vs paracetamol Mean RR 2.00, 95% CI 1.05 to
withdrawals due duration 13.1 3.81, p<0.05.
to AEs weeks (range Favours paracetamol
1-104 weeks)
444,444
Number of 1 RCT NSAIDs vs paracetamol 6 months NS
withdrawals due (N=581) (end of
to AEs treatment)
Table 152: Rescue medication

Rescue
medication use
as Assessment
Overall use of 1 N of 1 trial NSAIDs vs paracetamol n/a 7.5 (paracetamol) versus
escape analgesia (March et al. 1.0 (NSAIDs), p=0.013
(median number 1041-45), N=25 Favours NSAIDs
of tablets/week)
9.1.7 Evidence statements: paracetamol versus opioids, and paracetamol-opioid

combinations
Table 153: Symptoms: Pain

Paracetamol vs opioids
34
reduction in knee pain, 1 RCT N=20 Paracetamol vs 120 mins -35.0
VAS (change from tramadol post- (paracetamol)
baseline) intervention and -14.0
(tramadol)
Paracetamol
better
Paracetamol vs paracetamol-opioids
42
pain reduction (patient 1 RCT N=234 paracetamol vs 3 days NS
diary scores) codeine-paracetamol
243
pain reduction (VAS) 1 RCT N=161 paracetamol vs 4 weeks NS
codeine-paracetamol
Paracetamol-opioids vs NSAIDs
341
Pain, VAS 1 RCT N=755 dextropropoxyphene- 4 weeks p < 0.05
paracetamol vs slow- Favours NSAID
release diclofenac
341
Pain (NHP scale) 1 RCT N=755 dextropropoxyphene- 4 weeks NS
paracetamol vs slow-
Osteoarthritis

release diclofenac
214
Reduced weight- 1 RCT N=22 dextropropoxyphene- 4 weeks P<0.05
bearing pain and paracetamol Favours NSAIDs
reduced night-time (distalgesic) vs
pain indomethacin or
sulindac
214
Day-time pain. 1 RCT N=22 dextropropoxyphene- 4 weeks NS
paracetamol
(distalgesic) vs
indomethacin or
sulindac

214
increased functional 1 RCT N=22 dextropropoxyphe 4 weeks Indomethacin:100%
activity ne-paracetamol (p<0.02)
(distalgesic) vs Sulindac: 100%
indomethacin or (p<0.01)
sulindac Distalgesic: 11%
Favours NSAIDs
214
reduced knee joint size 1 RCT N=22 dextropropoxyphe 4 weeks Indomethacin:
ne-paracetamol p<0.05
(distalgesic) vs Sulindac p<0.01
indomethacin or Favours NSAIDs
sulindac
341
Physical mobility (NHP 1 RCT N=755 dextropropoxyphe 4 weeks P<0.01
scale) ne-paracetamol vs Favours NSAID
slow-release
diclofenac
Opioids vs NSAIDs
60,60
Improvement in 1 MA 1 RCT, Tramadol vs 28 days (end 3.9 (tramadol) and
WOMAC total score N=108 diclofenac of treatment) 4.0 (diclofenac)
Both groups similar
Table 155: Symptoms: Stiffness

214
Morning stiffness 1 RCT N=22 dextropropoxyphe 4 weeks NS
ne-paracetamol
(distalgesic) vs
indomethacin or
sulindac
Osteoarthritis

Opioids vs NSAIDs
60,60
number of patients 1 MA 1 RCT, Tramadol vs 28 days (end NS
with at least moderate N=108 diclofenac of treatment)
improvement in global
assessment

34
number of patients 1 RCT N=20 Paracetamol vs 1 week 0% (paracetamol)
with AEs, nausea and tramadol and 20%
vomiting (tramadol)
Paracetamol
better
42
GI AEs 1 RCT N=234 paracetamol vs 3 days NS
codeine-paracetamol
243
number of AEs 1 RCT N=161 paracetamol vs 4 weeks 27.6%
codeine-paracetamol (paracetamol) vs
52.3% (codeine-
para); p<0.01
214
number of patients 1 RCT N=22 dextropropoxyphene 4 weeks 22% (distlgesic)
with AEs -paracetamol and both NSAIDs
(distalgesic) vs 0%
indomethacin or NSAIDs better
sulindac
214
new cases of 1 RCT N=22 dextropropoxyphene 4 weeks N=8 (distalgesic)
dyspepsia or gastritis -paracetamol and N=1 (sulindac)
(distalgesic) vs NSAIDs better
sulindac
214
new cases of 1 RCT N=22 dextropropoxyphene 4 weeks N=8 (distalgesic)
dyspepsia or gastritis -paracetamol and N=6
(distalgesic) vs (indomethacin)
indomethacin Both groups
similar
341
number of study 1 RCT N=755 dextropropoxyphene 4 weeks 24% (dextro-para)
completers with AEs -paracetamol vs and 13%
diarrhoea (0.5% vs slow-release (diclofenac); <0.01
38%) and diclofenac Favours dextro-
indigestion/epigastric para
pain (5% vs 11%; p <
0.01).
341
number of study 1 RCT N=755 dextropropoxyphene 4 weeks 0.5% (dextro-para)
completers with -paracetamol vs and 38%
diarrhoea slow-release (diclofenac); <0.01
Osteoarthritis

diclofenac Favours dextro-
para
341
number of study 1 RCT N=755 dextropropoxyphene 4 weeks 5% (dextro-para)
completers with -paracetamol vs and 11%
indigestion/epigastric slow-release (diclofenac); <0.01
pain diclofenac Favours dextro-
para
341
dizziness / light- 1 RCT N=755 dextropropoxyphene 4 weeks 8% (dextro-para)
headedness -paracetamol vs and 4%
slow-release (diclofenac); <0.05
diclofenac Favours NSAID
341
sleep disturbance / 1 RCT N=755 dextropropoxyphene 4 weeks 13% (dextro-para)
tiredness -paracetamol vs and 6%
slow-release (diclofenac); <0.01
diclofenac Favours NSAID
297
Gastric AEs; mean 1 RCT N=32 dextropropoxyphene 4 weeks All groups similar
overall chronic -paracetamol vs
gastritis index; mean indomethacin or
overall acute gastritis sulindac
grading
Opioids vs NSAIDs
60,60
proportion of patients 1 MA 1 RCT, Tramadol vs 28 days (end NS
with major AEs N=108 dclofenac of treatment)
60,60
Proportion of patients 1 MA 1 RCT, Tramadol vs 28 days (end RR 6.0, 95% CI 1.41
with minor AEs N=108 dclofenac of treatment) to 25.5
NSAIDs better

34
number of 1 RCT N=20 Paracetamol vs 1 week 0% (paracetamol)
withdrawals tramadol and 20% (tramadol)
Paracetamol better
243
withdrawals due to 1 RCT N=161 paracetamol vs 4 weeks 13.5%
study drug AEs in the codeine- (paracetamol) and
group paracetamol 50% (tramadol);
p<0.01
Paracetamol better
341
Withdrawals due to GI 1 RCT N=755 dextropropoxyphe 4 weeks 34% (dextro-para)
AEs ne-paracetamol vs and 44%
slow-release (diclofenac)
diclofenac Dextro-para better
341
Withdrawals due to 1 RCT N=755 dextropropoxyphe 4 weeks 1.5% (dextro-para)
Osteoarthritis

respiratory AEs ne-paracetamol vs and 3.5%
diclofenac Dextro-para better
341
Withdrawals due to 1 RCT N=755 dextropropoxyphe 4 weeks 42% (dextro-para)
CNS AEs ne-paracetamol vs and 23%
diclofenac NSAID better
341
Total number of 1 RCT N=755 dextropropoxyphe 4 weeks 17% (dextro-para)
withdrawals ne-paracetamol vs and 15%
diclofenac Both groups similar
9.1.8 Evidence statements: opioids

Knee
Opioid vs placebo
38,38
pain relief (VAS) 1 MA 6 RCTs, Opioids vs 2-4 weeks mean difference
N=1057 placebo 10.5, 95% CI 7.4 to
13.7
Favours opioids
Knee and/or hip
Opioid vs placebo
219
improvement in pain 1 RCT N=264 Tramadol vs 2 weeks p=0.01
(verbal rating scale) placebo Favours tramadol
during daily activities
219
during walking
219
during sleep
219
pain relief (VAS) 1 RCT N=264 Tramadol vs 2 weeks NS
placebo
Opioid-paraceatmol vs placebo
60,60
pain intensity 1 MA 3 RCTs Tramadol / Range 14-91 mean difference -
tramadol- days 8.47, 95% CI -12.1
paracetamol vs to -4.9, p<0.00001
placebo Favours
opiod/opioid-
paracetamol
Opiodis: Low strength vs high strength
37
Total daily pain score 1 RCT N=40. cohort 1 low dose 2 weeks (end Cohort 1: NS
(VAS) (patients who took at tramadol vs of treatment) Cohort 2: tramadol
least 1 dose in each pentazocine SS better
Osteoarthritis

period and had pain
scores for at least 4
days
Cohort 2 (patients
who took at least 1
dose in each period
and recorded pain
scores on less than 4
days unless they
withdrew due to lack
of efficacy
158
WOMAC Pain, change 1 RCT (N=1020) Tramadol 12 weeks (end 107.2 (tramadol)
from baseline 100mg vs of treatment) and 74.2
placebo (placebo), p<0.01
Favours tramadol
158
Arthritis Pain intensity in 1 RCT (N=1020) Tramadol 12 weeks (end 27.8 (tramadol)
the index joint, change 100mg vs of treatment) and 20.2 (placebo)
from baseline placebo Favours tramadol
158
WOMAC pain on walking 1 RCT (N=1020) Tramadol 12 weeks (end NS
on a flat surface, change 100mg vs of treatment)
from baseline; Arthritis placebo
Pain intensity in the non-
index joint, change from
baseline
158
Favours tramadol
158
WOMAC pain on walking 1 RCT (N=1020) Tramadol 12 weeks (end 20.5 (tramadol)
on a flat surface, change 200mg vs of treatment) and 13.6
from baseline placebo (placebo), p<0.01
Favours tramadol
158
the index joint, change 200mg vs of treatment) and 20.2
Favours tramadol
158
the non-index joint, 200mg vs of treatment) and 14.5
change from baseline placebo (placebo), p<0.01
Favours tramadol
158
Favours tramadol
158
Osteoarthritis

Favours tramadol
158
Favours tramadol
158
Favours tramadol
158
Favours tramadol
158
Favours tramadol
158
Favours tramadol
158
Favours tramadol

Knee and/or hip
Opioids vs placebo
158
WOMAC stiffness, 1 RCT (N=1020) Tramadol 100mg 12 weeks (end 43.0 (tramadol)
change from baseline vs placebo of treatment) and 32.2
(placebo), p<0.05
Favours tramadol
158
(placebo), p<0.01
Favours tramadol
158
(placebo), p<0.01
Favours tramadol
158
(placebo), p<0.05
Osteoarthritis

Favours tramadol
Opioids: Low strength vs high strength
37
morning stiffness 1 RCT N=40. low dose tramadol 2 weeks (end p=0.034
duration vs pentazocine of treatment) Favours tramadol
37
morning stiffness 1 RCT N=40. low dose tramadol 2 weeks (end NS
severity score. vs pentazocine of treatment)

Knee and/or hip
Opioids vs placebo
219
patient ratings of good 1 RCT N=264 Tramadol vs 2 weeks p=0.022
or better in their overall placebo Favours tramadol
assessment of treatment
219
observers ratings of 1 RCT N=264 Tramadol vs 2 weeks p=0.017
good or better in their placebo Favours tramadol
overall assessment of
treatment
219
number of patients 1 RCT N=264 Tramadol vs 2 weeks NS
reporting improvement placebo
in: climbing stairs,
getting out of bed and
rising from a chair
158
WOMAC physical 1 RCT (N=1020) Tramadol 100mg 12 weeks (end 331.7 (tramadol)
function, change from vs placebo of treatment) and 234.3
baseline (331.7 and (placebo), p<0.05
234.3 Favours tramadol
158
WOMAC total, change 1 RCT (N=1020) Tramadol 100mg 12 weeks (end 481.5 (tramadol)
from baseline vs placebo of treatment) and 340.5
(placebo), p<0.01
Favours tramadol
158
baseline (placebo), p<0.01
Favours tramadol
158
(placebo), p<0.01
Favours tramadol
158
Favours tramadol
158
(placebo), p<0.01
Osteoarthritis

Favours tramadol
158
Favours tramadol
158
(placebo), p<0.05
Favours tramadol
Opioids / opioid-paracetamol vs placebo
60,60
at least moderate 1 MA 4 RCTs, tramadol/ Range 14-91 RR 1.4, 95% CI 1.2
improvement in global N=793 tramadol- days to 1.6, p<0.00001
assessment paracetamol vs Favours tramadol
placebo
37
patient’s overall 1 RCT N=40. low dose tramadol 2 weeks (end p=0.003
assessment of treatment vs pentazocine of treatment) Favours tramadol

Knee and/or hip
Opioids vs placebo
158
Physician’s Global 1 RCT (N=1020) Tramadol 100mg 12 weeks (end 22.9 (tramadol)
Assessment of Disease vs placebo of treatment) and 17.2
Activity, change from (placebo), p<0.05
baseline Favours tramadol
158
Patient’s Global 1 RCT (N=1020) Tramadol 100mg 12 weeks (end NS
Assessment of Disease vs placebo of treatment)
Activity
158
158
Patient’s Global 1 RCT (N=1020) Tramadol 200mg 12 weeks (end 21.8 (tramadol)
Activity (placebo), p<0.01
Favours tramadol
158
158
Patient’s Global 1 RCT (N=1020) Tramadol 300mg 12 weeks (end 23.5 (tramadol)
Activity (placebo), p<0.01
Osteoarthritis

Favours tramadol
158
158
Patient’s Global 1 RCT (N=1020) Tramadol 400mg 12 weeks (end NS
Assessment of Disease vs placebo of treatment)
Activity
Opioids / opioid-paracetamol vs palcebo
60,60
At least moderate 1 MA 4 RCTs, tramadol/ Range 14-91 RR 1.4, 95% CI 1.2
improvement in global N=793 tramadol- days to 1.6, p<0.
assessment paracetamol vs Favours tramadol
placebo

Knee and/or hip
Opioids vs placebo
158
Sleep quality, trouble 1 RCT (N=1020) Tramadol 100mg 12 weeks (end All p<0.05
falling asleep, awakened vs placebo of treatment) Favours tramadol
by pain in the night and
in the morning, the need
for sleep medication
158
SF-36 physical and 1 RCT (N=1020) Tramadol 100mg 12 weeks (end NS
mental components, vs placebo of treatment)
158
in the morning
158
mental components; The vs placebo of treatment)
need for sleep
medication, change from
baseline
158
in the morning
158
mental components; The vs placebo of treatment)
need for sleep
medication, change from
baseline
158
by pain in the night
Osteoarthritis

158
mental component; vs placebo of treatment)
Being awakened by pain
in the morning; The need
for sleep medication,
Table 164: Adverse Events (AEs) and withdrawals

Adverse events and
withdrawals as Assessment Outcome / Effect
Knee and/or hip
Opioids vs placebo
38,38
Withdrawal rate 1 MA Opiodis vs placebo Not Opioids had high
mentioned withdrawal rates
(20-50%)
158
Withdrawals due to AEs 1 RCT (N=1020) Tramadol 100mg vs 12 weeks (end 14% (tramadol)
placebo of treatment) and 10% (placebo)
Favours placebo
158
Number of patients 1 RCT (N=1020) Tramadol 100mg vs 12 weeks (end 71% (tramadol)
reporting at least 1 AE placebo of treatment) and 56% (placebo)
Favours placebo
158
Number of patients 1 RCT (N=1020) Tramadol 100mg vs 12 weeks (end 1.5% (tramadol)
reporting at least 1 SAE placebo of treatment) and 1% (placebo)
Favours placebo
158
Favours placebo
158
Favours placebo
158
Number of patients 1 RCT (N=1020) Tramadol 200mg vs 12 weeks (end 2% (tramadol) and
reporting at least 1 SAE placebo of treatment) 1% (placebo)
Favours placebo
158
Favours placebo
158
Favours placebo
158
Number of patients 1 RCT (N=1020) Tramadol 300mg vs 12 weeks (end 1.5% (tramadol)
reporting at least 1 SAE placebo of treatment) and 1% (placebo)
Favours placebo
158
Favours placebo
Osteoarthritis
Adverse events and

withdrawals as Assessment Outcome / Effect
158
Favours placebo
158
Number of patients 1 RCT (N=1020) Tramadol 400mg vs 12 weeks (end 3% (tramadol) and
reporting at least 1 SAE placebo of treatment) 1% (placebo)
Favours placebo
Opioids / opioid-paracetamol vs placebo
60,60
minor AEs). 1 MA 4 RCTs, tramadol/ tramadol- Range 14-91 mean difference
N=953 paracetamol vs days 2.17, 95% CI 1.8 to
placebo 2.7, p<0.00001
Favours placebo
219
Percentage of patients 1 RCT N=264 high dose tramadol 2 weeks (end all p≤0.001
experiencing AEs, vs of study) Favours
nausea, vomiting and dextropropoxyphen dextropropoxyphe
the percentage of e ne
withdrawals due to AEs
219
percentage of patients 1 RCT N=264 high dose tramadol 2 weeks (end NS
experiencing vs of study)
constipation dextropropoxyphen
e
37
numbers of patients 1 RCT N=40. low dose tramadol 2 weeks (end No p-values given
with AEs and nausea, vs pentazocine of treatment) Favours tramadol
patient withdrawals
due to AEs and
treatment failure
37
number of patients who 1 RCT N=40. low dose tramadol 2 weeks (end No p-values given
experienced vomiting vs pentazocine of treatment) Favours
and diarrhoea pentazocine

Knee and/or hip
Opioids vs placebo
158
Rescue medication use 1 RCT (N=1020) Tramadol 100mg vs 12 weeks (end 3% (tramadol) and
placebo of treatment) 7% (placebo)
Favours tramadol
158
Rescue medication use 1 RCT (N=1020) Tramadol 200mg vs 12 weeks (end 3% (tramadol) and
placebo of treatment) 7% (placebo)
Favours placebo
158
Rescue medication use 1 RCT (N=1020) Tramadol 300mg vs 12 weeks (end 1.5% (tramadol)
placebo of treatment) and 7% (placebo);
p<0.05
Favours placebo
158
Rescue medication use 1 RCT (N=1020) Tramadol 400mg vs 12 weeks (end 2.5% (tramadol)
and 7% (placebo);
Osteoarthritis

placebo of treatment) p<0.05
Favours placebo
9.1.9 Evidence statements: paracetamol versus placebo

Knee
185
WOMAC Pain (change 1 RCT (N=325) Paracetamol vs 6 months (end NS
from baseline) placebo of treatment)
Knee or hip
459
Pain response 1 MA , 1 RCT Paracetamol vs Range: 7 days RR 8.0, 95% CI
placebo to 12 weeks 2.08 to 30.73,
p=0.002
Favours
paracetamol
459
Pain response 1 MA , 3 RCTs Paracetamol vs Range: 7 days SMD –0.11, 95% CI
placebo to 12 weeks –0.22 to –0.01,
p=0.03
Favours
paracetamol
459
Pain on motion and 1 MA , 1 RCT Paracetamol vs Range: 7 days RR 3.75, 95% CI
placebo to 12 weeks 1.48 to 9.52,
p=0.005
Favours
paracetamol
459
Day pain 1 MA , 1 RCT Paracetamol vs Range: 7 days SMD -0.29, 95% CI
p=0.01
Favours
paracetamol
459
Night pain 1 MA , 1 RCT Paracetamol vs Range: 7 days SMD –0.28, 95% CI
p=0.02
Favours
paracetamol
459
MDHAQ VAS pain 1 MA , 2 RCTs Paracetamol vs Range: 7 days SMD –0.18, 95% CI
p=0.02
Favours
paracetamol
459
Overall pain 1 MA , 5 RCTs Paracetamol vs Range: 7 days SMD –0.13, 95% CI
p=0.005
Favours
paracetamol
Osteoarthritis

459
WOMAC pain; 1 MA , 1 RCT Paracetamol vs Range: 7 days NS
Lequesne pain; pain at placebo to 12 weeks
rest; pain on passive
motion
7
WOMAC pain (average 1 RCT (N=483) Paracetamol ER Over 12 (-26.5 and -19.6
change from baseline) 1950 mg/day vs weeks, end of respectively,
placebo treatment p=0.012
Favours
paracetamol
7
WOMAC pain (average 1 RCT (N=483) Paracetamol ER Over 12 NS
change from baseline) 3900 mg/day vs weeks, end of
placebo treatment

Knee or hip
459
WOMAC stiffness; 1 MA , 1 RCT Paracetamol vs Range: 7 days NS
stiffness at rest placebo to 12 weeks
7
WOMAC stiffness 1 RCT (N=483) Paracetamol ER Over 12 NS
1950 mg/day vs weeks, end of
placebo treatment
7
WOMAC stiffness 1 RCT (N=483) Paracetamol ER Over 12 NS
3900 mg/day vs weeks, end of
placebo treatment

Knee
185
Lequesne’s Index 1 RCT (N=325) Paracetamol vs 6 months (end NS
(change from baseline); placebo of treatment).
WOMAC total (change
from baseline);
WOMAC physical
function (change from
baseline); OARSI-A
responders.
Knee or hip
459
Physician’s global 1 MA , 1 RCT Paracetamol vs Range: 7 days RR 20.0, 95% CI
assessment of placebo to 12 weeks 2.95 to 135.75,
therapeutic response p=0.002
Favours
paracetamol
459
Patient’s global 1 MA , 1 RCT Paracetamol vs Range: 7 days RR 18.0, 95% CI
assessment of placebo to 12 weeks 2.66 to 121.63,
therapeutic response p=0.003
Favours
Osteoarthritis

paracetamol
459
WOMAC function 1 MA , 2 RCT Paracetamol vs Range: 7 days NS
placebo to 12 weeks
459
WOMAC total 1 MA , 3 RCTs Paracetamol vs Range: 7 days NS
placebo to 12 weeks
459
Lequesne function; 1 MA , 1 RCT Paracetamol vs Range: 7 days NS
Lequesne total; placebo to 12 weeks
Lequesne subset of
walking; 50-foot walk
time
7
WOMAC total (average 1 RCT (N=483) Paracetamol ER Over 12 24.5 (paracetamol)
change from baseline) 3900 mg/day vs weeks, end of and -18.6
placebo treatment (placebo), p<0.05
Favours
paracetamol
7
WOMAC physical 1 RCT (N=483) Paracetamol ER Over 12 -24.9
function (average 3900 mg/day vs weeks, end of (paracetamol) and
change from baseline) placebo treatment -17.8 (placebo),
p=0.016
Favours
paracetamol
7
WOMAC total (average 1 RCT (N=483) Paracetamol ER Over 12 NS
change from baseline); 1950 mg/day vs weeks, end of
WOMAC physical placebo treatment
function (average
change from baseline)

Knee or hip
459
Patient’s global 1 MA , 1 RCT Paracetamol vs Range: 7 days NS
assessment of Knee placebo to 12 weeks
osteoarthritis in the last
24 hours
7
Patient global 1 RCT (N=483) Paracetamol ER Over 12 p=0.015
assessment of response 1950 mg/day vs weeks, end of Favours
to therapy (average placebo treatment paracetamol
7
Patient global 1 RCT (N=483) Paracetamol ER Over 12 P=0.024
assessment of response 1950 mg/day vs weeks, end of Favours
to therapy (average placebo treatment paracetamol

Knee or hip
Osteoarthritis

166
Modified version of the 1 RCT Paracetamol vs Range: 7 days All p<0.05
AIMS-2 questionnaire: placebo to 12 weeks
subsets of mobility
level, household tasks,
walking and bending
166
Modified version of the 1 RCT Paracetamol vs NS
AIMS-2 questionnaire: placebo
all other subsets
Table 171: Adverse Events (AEs)

Knee
185
Number of patients 1 RCT (N=325) Paracetamol vs 6 months (end Both groups
with AEs; Number of placebo of treatment). similar
patients with GI AEs
Knee or hip
Total number of 1 MA459, 6 RCTs Paracetamol vs Range: 7 NS

patients reporting placebo days to 12
any AE; total number weeks
of withdrawals due to
toxicity.
Number of patients 1 RCT 7 (N=483) Paracetamol ER Over 12 NS

with AEs and SAEs 3900 mg/day vs weeks, end
placebo of treatment
Number of patients 1 RCT 7 (N=483) Paracetamol ER Over 12 NS

with AEs and SAEs. 1950 mg/day vs weeks, end
placebo of treatment
GI AEs 3 RCTs8,309,361 in Paracetamol vs Range: 7 NS

the SR459 placebo days to 12
weeks
GI AEs 1 RCT166 Paracetamol vs Range: 7 20.9%

placebo days to 12 (paracetamol)
weeks and 17.4%
(placebo). Both
groups similar

Knee
185
Use of rescue analgesia, 1 RCT (N=325) Paracetamol vs Over 6 21% (paracetamol)
% completers not using placebo months (end and 9% (placebo),
rescue medication of treatment). p=0.045 over 6
months (end of
Osteoarthritis

study)
Favours
paracetamol
Knee or hip
Rescue medication 1 RCT 7 (N=483) Paracetamol ER Over 12 NS

(number of capsules 3900 mg/day vs weeks, end
taken). placebo of treatment
Rescue medication 1 RCT 7 (N=483) Paracetamol ER Over 12 NS

(number of capsules 1950 mg/day vs weeks, end
taken). placebo of treatment

Knee
185
Withdrawals due to lack 1 RCT (N=325) Paracetamol vs Over 6 N=5 (paracetamol)
of efficacy (N=5 and placebo months (end and N=8 (placebo)
N=8 respectively) of treatment). Both groups
similar
185
Withdrawals due to AEs 1 RCT (N=325) Paracetamol vs Over 6 N=12
placebo months (end (paracetamol) and
of treatment). N=9 (placebo)
Both groups
similar
Knee or hip
459
Total number of 1 MA , 6 RCTs Paracetamol vs Range: 7 days NS
withdrawals due to placebo to 12 weeks
toxicity.
9.1.10 Evidence statements: tricyclics, SSRIs and SNRIs
Symptoms: pain
One RCT 412 (N=7) found that when Imipramine was given as the first treatment, the pain severity
score (measured change from baseline) improved when measured after imipramine treatment (-0.8)
but stayed the same when measured after placebo. (1+)
The same RCT 412 (N=7) found that when placebo was given as the first treatment, the pain score
stayed the same when measured after imipramine treatment and after placebo. (1+)
Symptoms: Function
One RCT 412 (N=7) when Imipramine was given as the first treatment, function score and grip strength
(measured change from baseline) improved when measured after imipramine treatment (-0.4 and
+19 mmHg respectively) but stayed the same when measured after placebo. (1+)
Osteoarthritis
The same RCT 412 (N=7) found that when placebo was given as the first treatment, function score
stayed the same when measured after imipramine treatment and after placebo. However, grip
strength increased after treatment with imipramine and after placebo, the increase being greater
after imipramine (+42.5 and +12.5 mmHg respectively). (1+)
Global assessment
One RCT 412 (N=7) found that when Imipramine was given as the first treatment, most of the patients
and physicians preferred imipramine to placebo (3 out of 4 patients for both). (1+)
The same RCT 412 (N=7) found that when placebo was given as the first treatment, no patients
preferred imipramine to placebo. (1+)

There is a good amount of evidence from RCTs on the efficacy of paracetamol in knee osteoarthritis,
with less evidence supporting its use in osteoarthritis of other sites. The long-term safety data on
paracetamol from observational studies is reassuring. The GDG noted that patients commonly use
infrequent dosing of paracetamol which may lead to inefficacy. There is limited data on the efficacy
of paracetamol used in combination with other pharmacological therapies, and most such data is
drawn from studies where paracetamol is used as “escape” analgesia.
The evidence supporting the use of opioid analgesia in osteoarthritis is poor, and it must be noted
there are virtually no good studies using these agents in peripheral joint osteoarthritis patients.
There is little evidence to suggest that dose escalation of these agents is effective. There is also little
data comparing different opioid formulations or routes of administration. Toxicity remains a concern
with opioid use, especially in the elderly. Constipation, nausea, itchiness, drowsiness and confusion
remain important side-effects to be considered.
There is no good evidence to support the use of low dose tricyclic agents for osteoarthritis pain.
However, consideration of sleep and mood disturbance is part of the assessment of the osteoarthritis
patient and appropriate pharmacological therapy may be warranted. The reader is also referred to
the NICE depression guideline.324

Update 2014
However, the GDG would like to draw attention to the findings of the evidence review on the efficacy
of paracetamol that was presented in the consultation version of the guideline. That review
identified reduced efficacy of paracetamol in the management of osteoarthritis compared with what
was previously thought. The GDG believes that this information should be taken into account in
routine prescribing practice until the intended full review of evidence on the pharmacological
management of osteoarthritis is published (see the NICE website for further details).
22.Healthcare professionals should consider offering paracetamol for pain relief in addition to core
treatments (see Figure 3 in section 4.1.2); regular dosing may be required. Paracetamol and/or
topical non-steroidal anti-inflammatory drugs (NSAIDs) should be considered ahead of oral
NSAIDs, cyclo-oxygenase-2 (COX-2) inhibitors or opioids. [2008]
Osteoarthritis
23.If paracetamol or topical NSAIDs are insufficient for pain relief for people with osteoarthritis,
then the addition of opioid analgesics should be considered. Risks and benefits should be
considered, particularly in older people. [2008]
9.2 Topical treatments

Topical NSAIDs, capsaicin and rubefacients and are widely used to treat osteoarthritis.
After topical application therapeutic levels of NSAIDs can be demonstrated in synovial fluid, muscles
and fasciae. They may have their pharmacological effects on both intra-and extra-articular structures
122,264,388
. It is assumed that their mechanism of action is similar to that of oral NSAIDs. Topical NSAIDs
produce a maximal plasma NSAID concentration of only 15% that achieved following oral
administration of a similar dose 122,187. Thus, it would be expected that topical NSAIDs would have far
fewer systematic side effects than oral NSAIDs. Even if their pain relieving effect is less than that of
oral NSAIDs they may be an attractive option for the treatment of osteoarthritis because they will
produce fewer NSAID related adverse effects.
It is possible that the act of rubbing and expectation of benefit may also contribute to any
therapeutic effect from topical preparations 11,467. This may partially account for the continued
popularity of rubefacients. Rubefacients produce counter-irritation of the skin that may have some
pain relieving effect in musculoskeletal disorders.
Capsaicin is derived from chilli peppers. As well as a counter-irritant effect it depletes

neurotransmitters in sensory terminals reducing the transmission of painful stimuli. There may be a
delay of some days for the effects of topical capsaicin to be evident, perhaps due to this progressive
neurotransmitter depletion.

We looked for studies that investigated the efficacy and safety of topical agents
(NSAIDs/capsaicin/rubefacients) compared with oral NSAIDs or placebo with respect to symptoms,
function and quality of life in adults with osteoarthritis. Two systematic reviews and meta-analyses
264,457
were found on topical NSAIDs and 10 additional RCTs 3,5,106,293,330,390,391,409,415,460 on topical
NSAIDs, capsaicin and rubefacients.
Both of the meta-analyses assessed the RCTs for quality and pooled together all data for the
outcomes of symptoms, function and AEs. However, the outcome of quality of life was not reported.
No QoL data was reported by the individual trials in the Towheed 457,458 MA, however QoL was
reported in the individual RCTs included in the Lin 264 MA. Results for quality of life have therefore
been taken from the individual RCTs included in this systematic review.
Topical NSAIDs
Two SRs/MAS 264,457 and 2 RCTs 330,460 were found on topical NSAIDs.
The first MA (Lin et al) 264 included 13 RCTs (with N=1983 participants) that focused on comparisons
between topical NSAIDs versus placebo or oral NSAIDs in patients with osteoarthritis. All RCTs were
randomised and double-blind. Studies included in the analysis differed with respect to:
 Osteoarthritis site (eight RCTs knee osteoarthritis; three RCTs hand osteoarthritis; one RCT hip,
knee and hand osteoarthritis; one RCT hip and knee osteoarthritis)
Osteoarthritis
 Type of topical NSAID used

 Type of oral NSAID used
 Treatment regimen
 Trial design (two RCTs cross-over; 11 RCTs parallel group studies), size and length.
The second MA (Towheed et al) 457,458 included four RCTs (with N=1412 participants) that focused on
comparisons between topical diclofenac in DMSO carrier versus placebo or oral diclofenac in patients
with knee osteoarthritis. All RCTs were randomised, double-blind parallel group studies. Studies
included in the analysis differed with respect to:
 Treatment regimen (three RCTs versus placebo, 50 drops 4 times daily; one RCT versus oral
Diclofenac, 50 drops 3 times daily)
The two RCTs not included in the systematic review focused on the outcomes of symptoms, function
and quality of life in patients with knee osteoarthritis. They were both parallel group studies and
were methodologically sound (randomised, double-blind, ITT analysis). However, they differed in
terms of: study intervention, sample size and study duration.
Topical capsaicin
Four RCTs were found on topical capsaicin versus placebo (given 4 times daily) and focused on the
outcomes of symptoms, function and quality of life in patients with osteoarthritis. All trials were
parallel group studies and were methodologically sound.
However, they differed in terms of: osteoarthritis site, sample size and study duration. One RCT 5
looked at 113 patients with knee, ankle, elbow, wrist and shoulder osteoarthritis and treatment
lasted for 12 weeks. The second RCT 106 looked at 70 patients with knee osteoarthritis and treatment
lasted for 4 weeks. The third RCT 293 looked at 200 patients with knee, hip, shoulder and hand
osteoarthritis and treatment lasted for 6 weeks. The fourth RCT 409 looked at 59 patients with hand
osteoarthritis and treatment lasted for 9 weeks
Topical Rubefacients
Four RCTs were found that focused on topical rubefacients versus placebo and focused on the
outcomes of symptoms, function and quality of life in patients with osteoarthritis. All trials were
methodologically sound (randomised and double-blind, two RCTs also included ITT analysis) 390,415.
However, they differed in terms of: osteoarthritis site, trial design, sample size, study duration and
study intervention. One RC 3 compared trolamine salicylate to placebo in 26 patients with knee
osteoarthritis and treatment lasted for 7 days. The second RCT 390 compared trolamine salicylate to
placebo in 50 patients with hand osteoarthritis and treatment was a single application. The third RCT
391
compared trolamine salicylate to placebo in 86 patients with hand osteoarthritis and treatment
was a single application. The fourth RCT 415 compared copper salicylate to placebo in 116 patients
with knee and/or hip osteoarthritis and treatment lasted for 4 weeks. 2 of the RCTs were parallel
group studies 391,415 and the other 2 RCTs 3,390 were cross-over design, both of which included a wash-
out period between cross-over treatments.
Osteoarthritis
9.2.3 Evidence Statements: topical NSAIDs

Assessment
Knee osteoarthritis
457,458
WOMAC Pain 1 MA 3 Topical diclofenac vs end of SMD –0.33, 95% CI –
RCTs (N=697) placebo treatment 0.48 to –0.18, p<0.0001
Favours topical
Pennsaid
457,458
WOMAC Pain at end 1 MA 1 Topical diclofenac vs end of NS
of treatment RCT (N=622) oral diclofenac treatment
330
Pain on movement, 1 RCT N=238 Topical diclofenac vs days 1-14 and Day 1-14: p=0.02
VAS (reduction from placebo days 8-21 (end Day 8-21: p=0.005
baseline) of treatment)
330
Pain Intensity, VAS 1 RCT N=238 Topical diclofenac vs weeks 1, 2 Week 1: p=0.03
(reduction from placebo and 3 (end of Week 2: p=0.0002
baseline) treatment), Week 3: p=0.006
330
WOMAC Pain 1 RCT N=238 Topical diclofenac vs weeks 2 and 3 Week 2: p<0.0001
(reduction from placebo (end of Week 3: p=0.0002
baseline) treatment),
330
Pain on movement, 1 RCT N=238 Topical diclofenac vs days 1-7; NS
VAS (reduction from placebo
baseline)
330
Spontaneous Pain, 1 RCT N=238 Topical diclofenac vs days 1-7 and NS
scale 0-3 (reduction placebo days 8-21;
from baseline)
330
Pain relief (scale 0-4) 1 RCT N=238 Topical diclofenac vs days 1-7 and NS
placebo days 8-21;
330
WOMAC Pain 1 RCT N=238 Topical diclofenac vs Week 1 NS
(reduction from placebo
baseline).
460
Pain at rest 1 RCT N=50 Topical ibuprofen vs 4 weeks Topical ibuprofen
placebo (interim) and better than placebo
8 weeks (end
of treatment);
460
Pain on motion 1 RCT N=50 Topical ibuprofen vs 4 weeks Topical ibuprofen
8 weeks (end
of treatment);
460
Overall pain 1 RCT N=50 Topical ibuprofen vs 4 weeks Topical ibuprofen
8 weeks (end
of treatment).
Knee or hand or mixed sites
264
Pain reduction (from 1 MA Week Topical NSAIDs vs week 1 and Week 1: Effect size
baseline) 1: 7 RCTs placebo week 2 0.41, 95% CI 0.16 to
(N=1000). 0.66, p≤0.05
Osteoarthritis
Assessment
Week 2: 6 Week 2: Effect size
RCTs (N=893) 0.40, 95% CI 0.15 to
0.65, p≤0.05
Favours topical NSAIDs
264
Pain reduction (from 1 MA Week Topical NSAIDs vs week 3 and NS
baseline) 3: 2 RCTs placebo week 4
(N=442). Week
4: 3 RCTs
(N=558)

Assessment
Knee osteoarthritis
457,458
WOMAC Stiffness 1 MA 3 Topical diclofenac vs end of SMD –0.30, 95% CI –
RCTs (N=696) placebo treatment 0.45 to –0.15, p<0.0001
Favours topical
pennsaid
457,458
WOMAC Stiffness 1 MA 1 Topical diclofenac vs end of NS
RCT (N=622) oral diclofenac treatment
264
Stiffness reduction 1 MA Week Topical NSAIDs vs week 1 Week 1: Effect size
(from baseline) 1: 1 RCT placebo 0.64, 95% CI 0.19 to
(N=74). 1.09, p≤0.05
264
Stiffness reduction 1 MA Week Topical NSAIDs vs week 24 NS
(from baseline) 2: 1 RCT placebo
(N=81).
Table 176: Symptoms: Patient Function

Assessment
Function outcome Reference Intervention time Outcome / Effect size
Knee osteoarthritis
457,458
WOMAC Physical 1 MA 3 Topical Pennsaid end of SMD –0.35, 95% CI –
Function RCTs (N=696) (Diclofenac) vs treatment 0.50 to –0.20, p<0.0001
placebo Favours topical
Pennsaid
457,458
WOMAC Physical 1 MA 1 Topical Pennsaid end of NS
Function RCT (N=622) (Diclofenac) vs oral treatment
diclofenac
330
WOMAC physical 1 RCT N=238 Topical Diclofenac vs weeks 2 and 3 Week 2: p=0.002
function (reduction placebo (end of Week 3: p=0.0004
330
WOMAC physical 1 RCT N=238 Topical Diclofenac vs Week 1 NS
function (reduction placebo
from baseline)
Osteoarthritis
Assessment
460
Lequesne Index 1 RCT N=50 Topical Ibuprofen vs 4 weeks Topical ibuprofen
placebo (interim) and better than palcebo
8 weeks (end
of treatment)
264
Improvements in 1 MA Week Topical NSAIDs vs week 1 and Week 1: Effect size
function (from 1: 4 RCTs placebo week 2 0.37, 95% CI 0.20 to
baseline) (N=556). 0.53, p≤0.05
Week 2: 4 Week 2: Effect size
RCTs (N=540). 0.35, 95% CI 0.19 to
0.53, p≤0.05
264
Improvements in 1 MA week Topical NSAIDs vs week 3 and NS
function (from 3: 1 RCT placebo week 4
baseline) (N=208)
week 4: 1 RCT
(N=208).
264
Improvements in 1 MA week Topical NSAIDs vs weeks 1, 2, 3 NS
function (from 1 and 2 1 RCT oral NSAIDs and 4
baseline) (N=208),
week 3: 2 RCTs
(N=529), week
4: 1 RCT,
N=208.

Global assessment Assessment
Knee osteoarthritis
457,458
Patient global 1 MA 3 Topical Pennsaid end of SMD –0.39, 95% CI –
assessment RCTs (N=689) (Diclofenac) vs treatment 0.54 to –0.24, p<0.0001
placebo Favours topical
pennsaid
457,458
Patient global 1 MA 1 Topical Pennsaid end of NS
assessment RCT (N=622) (Diclofenac) vs oral treatment
diclofenac
330
Patient’s overall global 1 RCT N=238 Topical Diclofenac vs Over the 3 P=0.03
assessment of placebo weeks
treatment efficacy treatment
460
Investigator’s global 1 RCT N=50 Topical Ibuprofen vs 4 weeks Ibuprofen better than
assessment of efficacy placebo (interim) and placebo
(good or very good) 8 weeks (end
of treatment)
460
Patients global 1 RCT N=50 Topical Ibuprofen vs 4 weeks Ibuprofen better than
assessment of efficacy placebo (interim) and placebo
(good or very good) 8 weeks (end
of treatment)
Osteoarthritis

Assessment
QoL outcome Reference Intervention time Outcome / Effect size
169
SF-36 (all dimensions) 1 RCT in the Topical diclofenac vs week 2 (end NS
264
MA (N=74) placebo of treatment)

Assessment
AEs outcome Reference Intervention time Outcome / Effect size
Knee osteoarthritis
457,458
Minor skin dryness 1 MA 3 Topical diclofenac vs Over Minor skin dryness RR
RCTs placebo treatment 1.74, 95% CI 1.37 to
period 2.22
Favours topical
pennsaid
457,458
Paresthsia, Rash, Any 1 MA 3 Topical diclofenac vs Over NS
AEs, GI AEs RCTs placebo treatment
period
457,458
GI AEs 1 MA Topical diclofenac vs Over RR 0.72, 95% CI 0.59 to
1RCT oral diclofenac treatment 0.87
period Favours topical
pennsaid
457,458
Severe GI AEs 1 MA Topical diclofenac vs Over RR 0.35, 95% CI 0.17 to
pennsaid
457,458
Dry skin reactions 1 MA Topical diclofenac vs Over RR 20.8, 95% CI 7.7 to
period Favours oral diclofenac
457,458
Rash 1 MA Topical diclofenac vs Over RR 7.2, 95% CI 2.9 to
period Favours oral diclofenac
330
Total number of AEs 1 RCT N=238 Topical diclofenac vs Over both: 9%
placebo treatment
period
330
GI AEs 1 RCT N=238 Topical diclofenac vs Over 0% (topical)
placebo treatment 1.7% (placebo)
period
330
Skin AEs 1 RCT N=238 Topical diclofenac vs Over 2.9% (topical)
placebo treatment 2.5% (placebo)
period
460
AEs 1 RCT N=50 Topical ibuprofen vs Over None in either group
placebo treatment
period
264
Number of patients 1 MA Topical NSAIDs vs Over NS
Osteoarthritis
Assessment
with AEs; Number of (N=1108) placebo treatment
patients with GI AEs; period
Number of patients
with CNS AEs; Local
AEs – skin reactions
264
Local AEs – skin 1 MA Topical NSAIDs vs Over Rate Ratio 5.29, 95% CI
reactions (N=443) oral NSAIDs treatment 1.14 to 24.51, p≤0.05
period Favours oral NSAIDs
264
with AEs or GI AEs (N=764) oral NSAIDs treatment
period
264
with CNS AEs (N=443) oral NSAIDs treatment
period
Table 180: Study Withdrawals

Assessment
Knee osteoarthritis
457,458
Withdrawals due to 1 MA 3 Topical diclofenac vs Over NS
toxicity RCTs placebo treatment
period
457,458
Withdrawals due to 1 MA 1 Topical diclofenac vs Over RR 2.80, 95% CI 1.38 to
lack of efficacy RCT oral diclofenac treatment 5.67
period
457,458
Withdrawals due to 1 MA 1 Topical diclofenac vs Over NS
toxicity RCT oral diclofenac treatment
period
457,458
Total number of 1 MA 1 Topical diclofenac vs Over NS
withdrawals RCT oral diclofenac treatment
period
Total number of 1 RCT 1 RCT Topical diclofenac vs Over None in either group
330
withdrawals N=238 placebo treatment
period
460
Total number of 1 RCT N=50 Topical Ibuprofen vs Over None in either group
withdrawals placebo treatment
period
264
withdrawn due to AEs (N=1108) placebo treatment
period
264
withdrawn due to AEs (N=764) oral NSAIDs treatment
period
Osteoarthritis
Table 181: Other outcomes

Other outcomes Reference Intervention time size
264
Clinical response rate (% of 1 MA 2 Topical NSAIDs vs Week 1 Rate ratio 1.64, 95%
patients reporting at least RCTs placebo CI 1.26 to 2.13,
moderate to excellent or > (N=149) p≤0.05; NNT 3.3,
50% pain relief or 95% CI 2.3 to 6.2,
improvement in symptoms p≤0.05
264
Clinical response rate (% of 1 MA 1 Topical NSAIDs vs Week 2 Rate ratio 1.59, 95%
patients reporting at least RCT (N=152) placebo CI 1.30 to 1.95,
moderate to excellent or > p≤0.05; NNT 2.9,
50% pain relief or 95% CI 2.1 to 4.7,
improvement in symptoms p≤0.05
264
Clinical response rate (% of 1 MA 1 Topical NSAIDs vs Week 4 NS
patients reporting at least RCT (N=114) placebo
moderate to excellent or >
50% pain relief or
improvement in symptoms
264
Clinical response rate (% of 1 MA 1 Topical NSAIDs vs Oral Week 4 NS
patients reporting at least RCT (N=225) NSAIDs
moderate to excellent or >
50% pain relief or
improvement in symptoms
9.2.4 Evidence statements: topical capsaicin versus placebo

Assessment
Knee osteoarthritis
106
Pain, VAS (% reduction 1 RCT Topical capsaicin vs 1, 2 and 4 overall p=0.033
from baseline) (N=70) placebo weeks (end of
treatment)
106
Pain severity (Scale 0- 1 RCT Topical capsaicin vs 1, 2 and 4 overall p=0.020
4, % reduction from (N=70) placebo weeks (end of
baseline) treatment)
Hand
409
Articular tenderness 1 RCT Topical capsaicin vs week 3 and both: p=0.02
(tenderness units) (N=59) placebo week 9
409
Pain, VAS (% change 1 RCT Topical capsaicin vs week 1, 2, 3 6 NS
from baseline) (N=59) placebo and 9 (end of
treatment)
409
Articular tenderness 1 RCT Topical capsaicin vs week 1 and NS
(tenderness units) (N=59) placebo week 6 (mid
treatments).
Mixed (Knee, ankle, elbow, wrist, shoulder)
5
Pain, VAS (% of 1 RCT (N=113) Topical capsaicin vs weeks 4, 8 Week 4: p=0.003
patients improved) placebo and 12 (end of Week 8: p=0.011
Osteoarthritis
Assessment
treatment) Week 12: p=0.020
5
Tenderness on passive 1 RCT (N=113) Topical capsaicin vs weeks 8 and both p=0.03
motion (% of patients placebo 12 (end of
improved) treatment),
5
Tenderness on 1 RCT (N=113) Topical capsaicin vs weeks 4, 8 Week 4: p=0.003
palpation (% of placebo and 12 (end of Week 8: p=0.01
patients improved) treatment) Week 12: p=0.01
5
Pain, VAS (% of 1 RCT (N=113) Topical capsaicin vs week 1 and NS
patients improved) placebo week 2
Mixed (Knee, hip, shoulder, hand)
293
Pain (VAS) 1 RCT Topical capsaicin vs weeks 2, 3, 4, Topical capsaicin better
(N=200) placebo 5 and 6 (end than placebo
of treatment

Assessment
5
Reduction in morning 1 RCT (N=113) Topical capsaicin vs weeks 4, 8 NS
stiffness placebo and 12 (end of
treatment)
Table 184: Symptoms: Patient Function

Assessment
Hand
409
Grip strength (% 1 RCT Topical capsaicin vs week 9 (end p=0.046
change from baseline) (N=59) placebo of treatment)
409
Grip strength (% 1 RCT Topical capsaicin vs week 2 and week 2: 30.3 (topical)
change in baseline) (N=59) placebo week 6 and 15.6 (placebo)
week 6: 27.0 (topical)
and 11.6 (placebo)
409
Grip strength (% 1 RCT Topical capsaicin vs week 1 9.1 (topical) and 10.2
change in baseline) (N=59) placebo (placebo)
409
Functional assessment 1 RCT Topical capsaicin vs week 9 1.5 (topical) and 0.9
(% change in baseline) (N=59) placebo (placebo)

Knee osteoarthritis
106
Physicians’ global 1 RCT Topical capsaicin vs Week 1, 2 and overall p=0.023
assessment (% (N=70) placebo 4 (end of
reduction from treatment)
Osteoarthritis

baseline)

5
Physician’s global 1 RCT (N=113) Topical capsaicin vs week 4 (mid- week 4: p=0.042
evaluation (% of placebo treatment) week 12: p=0.026
patients improved) and week 12
(end of
treatment)
5
Patient’s global 1 RCT (N=113) Topical capsaicin vs week 4 (mid- week 4: p=0.023
evaluation (% of placebo treatment) week 12: p=0.028
patients improved) and week 12
(end of
treatment)
5
Physician’s global 1 RCT (N=113) Topical capsaicin vs weeks 1, 2 NS
evaluation (% of placebo and 8 (mid-
patients improved) treatments)
5
Patient’s global 1 RCT (N=113) Topical capsaicin vs weeks 1, 2 NS
evaluation (% of placebo and 8 (mid-
patients improved) treatments)

Assessment
QoL outcome Reference Intervention time Outcome / Effect size
5
Health assessment 1 RCT (N=113) Topical capsaicin vs weeks 4, 8 NS
questionnaire placebo and 12 (end of
treatment)

Assessment
Hand
409
Number of patients 1 RCT Topical capsaicin vs Over 9 weeks N=20, 69.0% (topical)
with AEs (N=59) placebo treatment and N=9, 30.0%
(placebo).

Assessment
Withdrawals outcome Reference Intervention time Outcome / Effect size
Knee osteoarthritis
106
number of 1 RCT Topical capsaicin vs Over N=1, 2.9% (topical) and
withdrawals (N=70) placebo treatment N=5, 14.3% (placebo)
period
Hand
409
Number of study 1 RCT Topical capsaicin vs Over N=4, 13.8% (topical)
withdrawals (N=59) placebo treatment and N=7, 23.3%
Osteoarthritis
Assessment
period (placebo).
5
Number of study 1 RCT (N=113) Topical capsaicin vs Over N=11, 19.3% (topical)
withdrawals placebo treatment and N=6, 10.7%
period (placebo)
5
Withdrawals due to 1 RCT (N=113) Topical capsaicin vs Over N=5, 8.7% (topical) and
AEs ( placebo treatment N=0, 0% (placebo)
period
5
Withdrawals due to 1 RCT (N=113) Topical capsaicin vs Over N=6, 10.5% (topical)
treatment failure placebo treatment and N=4, 7.5%
period (placebo).
293
number of 1 RCT Topical capsaicin vs Over both N=10, 20%
withdrawals (N=200) placebo treatment
period

Assessment
293
Daily use of analgesics 1 RCT Topical capsaicin vs Over Lower use for topical
(N=200) placebo treatment capsaicin patients than
period placebo
293
Patients favoured 1 RCT Topical capsaicin vs Over OR 2.4, 95% CI 1.2 to
staying on treatment (N=200) placebo treatment 5.1
capsaicin
9.2.5 Evidence statements: topical rubefacients

Assessment
Knee osteoarthritis
3
Pain (SDS), mean 1 RCT (N=26) trolamine salicylate 7 days NS
change after vs placebo
treatment
3
Pain (NRS), mean 1 RCT (N=26) trolamine salicylate 7 days NS
change after vs placebo
treatment
Hand
391
Pain intensity (1-5 1 RCT (N=86) trolamine salicylate 45 mins post- Right hand: p=0.04
scale) vs placebo treatment. Both hands averaged:
p=0.026
Osteoarthritis
Assessment
Dominant hand:
p=0.02
390
Pain severity (change 1 RCT (N=50) trolamine salicylate 0, 15, 20, 30, NS
from baseline vs placebo 45 and 120
mins after
treatment
391
Pain intensity 1 RCT (N=86) trolamine salicylate pooled for 30 NS
(change from vs placebo mins, 45 mins
baseline); and 120 mins
post-
intervention
391
Pain intensity (1-5 1 RCT (N=86) trolamine salicylate 30 mins and NS
scale) vs placebo 120 mins
post-
intervention
391
Pain intensity (1-5 1 RCT (N=86) trolamine salicylate 45 mins post- NS
scale) in the left hand vs placebo intervention.
Mixed (Knee and/or hip)
415
Pain at rest, VAS One RCT copper-salicylate vs end of NS
(change from (N=116) placebo treatment (4
baseline) weeks)
415
Pain on movement, One RCT copper-salicylate vs end of NS
VAS (change from (N=116) placebo treatment (4
baseline) weeks)

Assessment
Hand
391
Stiffness intensity 1 RCT (N=86) Trolamine salicylate pooled for 30 right hand: p=0.023
(change from mins, 45 mins both hands averaged:
baseline) and 120 mins p=0.028
post- dominant hand:
391
Stiffness intensity (1- 1 RCT (N=86) Trolamine salicylate 45 mins post right hand: p=0.016
5 scale) intervention both hands averaged:
p=0.024 dominant
hand: p=0.004
391
Stiffness intensity (1- 1 RCT (N=86) Trolamine salicylate 120 mins post right hand: p=0.026
5 scale) intervention both hands averaged:
p=0.026 dominant
hand: p=0.006
391
Stiffness intensity 1 RCT (N=86) Trolamine salicylate pooled for 30 NS
(change from mins, 45 mins
baseline) for the left and 120 mins
hand post-
intervention
Osteoarthritis
Assessment
391
Stiffness intensity (1- 1 RCT (N=86) Trolamine salicylate 30 mins and NS
5 scale) in the left 45 mins post-
hand intervention
390
stiffness relief 1 RCT (N=50) Trolamine salicylate 0, 15, 20, 30, NS
(change from 45 and 120
baseline) mins after
treatment

Assessment
Knee osteoarthritis
3
Degree of swelling 1 RCT (N=26) trolamine salicylate after 1 mm (trolamine)
(mm), mean change vs placebo treatment (7 and –8 mm (placebo),
days) p=0.009
Favours placebo
3
Joint tenderness 1 RCT (N=26) trolamine salicylate after NS
vs placebo treatment (7
days)
3
Range of motion 1 RCT (N=26) trolamine salicylate after NS
(Extension and vs placebo treatment (7
flexion, degrees); days)
3
Morning stiffness 1 RCT (N=26) trolamine salicylate after NS
vs placebo treatment (7
days)
3
Activity (pedometer 1 RCT (N=26) trolamine salicylate after NS
measurements, km) vs placebo treatment (7
days)

Knee osteoarthritis
3
Patient evaluation of 1 RCT (N=26) trolamine salicylate 7 days NS
relief vs placebo
3
Examiner evaluation 1 RCT (N=26) trolamine salicylate 7 days NS
of relief vs placebo
3
Patient preference 1 RCT (N=26) trolamine salicylate 7 days NS
vs placebo
415
Patient’s global One RCT copper-salicylate vs 4 weeks (end NS
assessment of (N=116) placebo of treatment)
treatment efficacy, 4-
point Likert Scale
(change from
baseline)
Osteoarthritis

415
Investigator’s global One RCT copper-salicylate vs 4 weeks (end NS
assessment of (N=116) placebo of treatment)
treatment efficacy, 4-
point Likert Scale
(change from
baseline)

Assessment
Knee osteoarthritis
3
Number of AEs 1 RCT (N=26) trolamine salicylate 7 days None reported for
vs placebo either group
Hand
390
Number of AEs 1 RCT (N=50) Trolamine salicylate Not N=2 (trolamine)
vs placebo mentioned N=1 (placebo)

415
Number of AEs One RCT copper-salicylate vs 4 weeks (end N=100 (copper
(N=116) placebo of treatment) salicylate)
N=58 (placebo);
p=0.002
Favours placebo

Withdrawal Assessment
outcomes Reference Intervention time Outcome / Effect size
Hand
390
Number of 1 RCT (N=50) Trolamine salicylate During N=1 (trolamine)
withdrawals vs placebo treatment N=0 (placebo)
390
Number of 1 RCT (N=50) Trolamine salicylate During Both: N=0
withdrawals due to vs placebo treatment
AEs
391
Number of 1 RCT (N=86) Trolamine salicylate During N=2 (trolamine)
withdrawals vs placebo treatment N=3 (placebo)

415
Number of One RCT copper-salicylate vs During 4 26% (copper-
withdrawals (N=116) placebo weeks salicylate)
treatment 17% (placebo)
415
Withdrawals due to One RCT copper-salicylate vs During 4 17% (copper-
AEs (N=116) placebo weeks salicylate)
treatment 1.7% (placebo)
Osteoarthritis
415
Withdrawals due to One RCT copper-salicylate vs During 4 5.2(copper-salicylate)
lack of efficacy. (N=116) placebo weeks 3.4(placebo)
treatment

415
Number of patients One RCT copper-salicylate vs During 4 NS
taking rescue (N=116) placebo weeks
medication treatment
(paracetamol)
9.2.6 Health economic evidence

We looked at studies that conducted economic evaluations involving topical NSAIDs, capsaicin or
rubefacients. Three papers, two from the UK and one from Australia, relevant to this question were
found and included as evidence. After the re-run search one further study was included.
Two UK papers from the early 1990s conducted cost minimisation analyses rather than full cost
effectiveness or cost utility analysis.
One UK paper compares oral ibuprofen (1200mg/day) to topical Traxam and oral Arthrotec
(diclofenac 50mg/misoprostol 200 mg one tablet twice daily) 347. The study considers the drug cost
of each treatment as well as the cost of ulcers caused by the treatment using a simple economic
model. It does not include other GI adverse events or CV adverse events. Including these would
make the oral NSAID appear more expensive. Ulcer incidence rates are estimated based on findings
in the literature, and some simple sensitivity analysis is undertaken around this. In conducting a cost
minimisation analysis the authors have implicitly assumed equal efficacy of the treatments, which
may not be appropriate. The duration considered in the study is one month.
Another UK study considers oral ibuprofen (1200mg/day) and topical piroxicam gel (1g three times
daily) 298. The cost per patient of each treatment is calculated using a decision tree which includes
ulcers and dyspepsia as adverse events. CV adverse events are not included. Adverse event rates are
estimated using data in the published literature. Importantly the efficacy of the treatments is
assumed to be equal and hence only costs are considered. The duration of the study is three
months.
The Australian study considers a number of different treatments for osteoarthritis, one of which is
topical capsaicin compared to placebo 413. The paper is generally well conducted. Data regarding the
effectiveness of capsaicin is taken from the literature (5,106). The transfer to utility (TTU) technique
was used to transform the pain improvement data available in trials into a Quality Adjusted Life Year
(QALY) gain. The paper assumes that capsaicin does not increase the risk of adverse events over the
levels experienced by the general population, and so the only costs included in the study are the
specific drugs cost. The study takes a one year time period and calculates the incremental cost
effectiveness ratio (ICER) of topical capsaicin compared to placebo.
It is of note that a study protocol for a trial assessing the costs and benefits associated with treating
patients with chronic knee pain with topical or ibuprofen was published in November 2005.
Osteoarthritis
One UK study which is yet to be published investigates oral ibuprofen compared to topical ibuprofen
in 585 patients with knee pain. The study had an RCT arm and a patient preference arm, and
includes 12 month and 24 month data.
9.2.7 Health economic evidence statements
Oral Ibuprofen versus Topical Traxam or Topical Piroxicam and Arthrotec
Table 197: Cost (1993£) of treating 1,000 patients for 1 month

Ibuprofen (1200mg/day) Traxam Arthrotec
41,408 7,319 17,924
Table 198: Cost (1991-1992£) per patients for 3 month

Ibuprofen (1200mg/day) Piroxicam (1g tid)
89.12 54.57
The tables above show the results of the two studies from the UK 298,347. They offer evidence that
treatment with topical NSAIDs is likely to be cheaper than treatment with oral NSAIDs. However it
must be noted that the studies are incomplete with regards to the adverse events included (neither
include CV adverse events, and not all GI adverse events are included). Including these adverse
events would result in topical NSAIDs leading to a higher cost saving compared to oral NSAIDs
providing topical NSAIDs result in fewer of these events than oral NSAIDs. Also the results of the
studies are of limited use with regards to cost effectiveness since a health outcome is not included.
Equal efficacy is assumed, but if oral NSAIDs are in actuality more effective, then there remains a
possibility that they could be considered cost effective despite being more expensive.
In summary, evidence suggests that treatment with topical NSAIDs will result in lower costs than
treatment with oral NSAIDs due to the higher prevalence of adverse events with oral NSAIDs. The
cost effectiveness of oral NSAIDs depends on their clinical efficacy compared to topical NSAIDs. If
oral NSAIDs are of equal efficacy compared to topical NSAIDs it is likely that topical NSAIDs would be
cost effective.
Topical Capsaicin versus Placebo
Table 199: Segal’s estimates of cost effectiveness

Mean QALY gain per Cost/QALY best
Program person Mean program cost estimate
Non-specific NSAIDs 0.043 Drug: $104/year $15,000 to infinity
(naproxen, diclofenac) Morbidity: $70/year
Cox 2s (Celecoxib) 0.043 Drug: $391/year $33,000 to infinity
Morbidity: $70/year
Topical Capsaicin 0.053 $236 $4,453
Glucosamine sulphate 0.052 $180 $3,462
The table above shows the cost effectiveness of a number of drugs as calculated by the Australian
study 413. NSAIDs, COX-2 inhibitors, and Glucosamine sulfate are included to allow some comparison
of cost effectiveness between the drugs, although each is only compared to placebo in the analysis,
rather than to each other. Where the cost effectiveness ratio is said to range “to infinity” this is
because the benefits of the drug are not assured.
Osteoarthritis
These results suggest that topical capsaicin brings more QALY gain than NSAIDs or COX-2 inhibitors
compared to placebo, while resulting in lower total costs than COX-2 inhibitors (although the total
costs are higher than for NSAIDs). Therefore capsaicin appears dominant compared to COX-2
inhibitors. The incremental cost effectiveness ratio between NSAIDs and topical capsaicin [(236-
174)/(0.053-0.043) = $6,200] suggests that topical capsaicin is likely to be cost effective compared to
NSAIDs. However the incremental cost effectiveness ratio between topical capsaicin and
glucosamine sulfate only shows borderline cost effectiveness (236-180)/(0.053-0.052) = $56,000 per
QALY. Because the cost of topical capsaicin is relatively low and QALY gains are accrued, the
incremental cost effectiveness ratio of $4,453 stated in Table 3 suggests the treatment is cost
effective compared to placebo.
Some care has to be taken with these results because of the relative lack of studies which show the
benefits of capsaicin and glucosamine sulfate. The transfer to utility approach for calculating QALY
gains has also been questioned in the literature. The study is also from an Australian perspective
which may not be transferable to a UK setting.
It is of interest that in the UK 45g of topical capsaicin costs £15.04. If this size tube was sufficient for
one month of treatment the UK yearly cost of treatment with topical capsaicin would be £180.48
(taking into account only drug costs). Some sources suggest this size tube would in fact not be
sufficient for one month of treatment (http://www.pharmac.govt.nz/pdf/0804.pdf). This is
significantly more expensive than the $236 cost stated by the Australian study, which equates to
£95.57, but does assume that the patient uses the treatment continuously for one year. Using this
cost, the incremental cost effectiveness ratio of topical capsaicin compared to placebo would be
(180.48/0.053) = £3,405 per QALY which is still relatively low.
However, in comparison to other drugs topical capsaicin appears likely to be closer to the cost of
COX-2 inhibitors, and significantly more expensive than some NSAIDs in a UK setting. In the UK
celecoxib costs £21.55 per 60-cap 100mg pack, suggesting a yearly drug cost of approximately
(21.55*12) £259 (BNF 51). Diclofenac sodium costs £1.52 for an 84-tab pack of 25mg suggesting a
yearly drug cost of approximately (1.52*12) £18.24, (BNF 51) although these estimates do not
include the adverse event costs of these drugs.
Given this, it is difficult to make reliable recommendations regarding topical capsaicin compared to
COX-2 inhibitors and NSAIDs based on this Australian data.
In summary, evidence from an Australian study suggests that topical capsaicin is cost effective
compared to placebo, since it brings QALY gains at relatively low cost.
Topical Ibuprofen versus oral ibuprofen
The study finds that the effectiveness of the two treatments is not statistically significantly different,
but that oral ibuprofen appears slightly better. Oral ibuprofen is generally a more expensive
treatment option, due to more gastroprotective drugs and cardiovascular drugs being prescribed
alongside it. Overall oral ibuprofen is generally found to be cost effective compared to topical
ibuprofen. However the authors note that the study considered a population at low risk of adverse
events and the prevalence of adverse events in the study was lower than expected. Given the risks
known to be associated with taking oral NSAIDs, it may be that in a higher risk population oral
NSAIDs would not be cost effective.
In summary:
 In a population at low risk of adverse events, oral ibuprofen is likely to be a cost effective
treatment compared to topical ibuprofen.
 Treatment with topical ibuprofen is likely to be cheaper than treatment with oral ibuprofen.
Osteoarthritis

A number of studies, mainly of knee osteoarthritis have shown short term (< four weeks) benefits
from topical NSAID gels, creams and ointments when compared to placebo. There are no data on
their long term effectiveness when compared to placebo. There are limited studies comparing other
topical gels, creams and ointments with oral NSAIDs. One study with three month follow up found
topical diclofenac in dimethyl sulfoxide to be equivalent to oral diclofenac for knee osteoarthritis
over three months.
The data from RCTs have demonstrated a reduction in non-serious adverse effects when compared
to oral NSAIDs, although topical preparations may produce local skin irritation. The RCT data do not
allow a conclusive judgement on whether using topical NSAIDs reduces the incidence of serious
NSAID related adverse effects. However, it seems logical that there may be a reduced risk given the
total dose of NSAID from topical application to one joint area is much less than when used orally.
Thus, since there are some data supporting the effectiveness of topical NSAIDs they are likely to be
preferred to using oral NSAIDs as early treatment for osteoarthritis, particularly for patients who do
not have widespread painful osteoarthritis. However there are no data comparing topical NSAIDs to
paracetamol or on the comparative risk and benefits from the long term use of oral or topical
NSAIDs.
Topical NSAIDs are relatively costly but are cost-effective given that they prevent or delay use of oral
NSAIDs with their associated serious adverse events. Most of the clinical evidence is for the
preparation of diclofenac in DMSO, but overall there is little evidence and the group did not find
sufficient justification to single out this brand in the recommendations. At the time of writing,
Pennsaid was not the cheapest alternative in this class.
There are limited data showing some positive effects from topical capsaicin, with short-term follow-
up. Although the evidence is limited to knee osteoarthritis, the GDG were aware of widespread use
in hand osteoarthritis as part of self-management and felt that the data on efficacy at the knee could
reasonably be extrapolated to the hand. No serious toxicity associated with capsaicin use has been
reported in the peer-reviewed literature. The evidence base, however, does not support the use of
rubefacients.
Topical treatments are used in self-management, which helps change health behaviour positively.
Often, people with osteoarthritis will use the topical treatment on top of daily paracetamol and
exercise to cope with flare-ups. This is in line with the evidence, which shows short-term benefit. As a
safe pharmaceutical option, topical NSAIDs were regarded by the GDG as one of the second-line
options for symptom relief after the core treatments. They have therefore been placed on an equal
footing with paracetamol.

Update 2014
However, the GDG would like to draw attention to the findings of the evidence review on the efficacy
of paracetamol that was presented in the consultation version of the guideline. That review
identified reduced efficacy of paracetamol in the management of osteoarthritis compared with what
was previously thought. The GDG believes that this information should be taken into account in
routine prescribing practice until the intended full review of evidence on the pharmacological
management of osteoarthritis is published (see the NICE website for further details).
Osteoarthritis
24.Consider NSAIDs for pain relief in addition to core treatments (see Figure 3 in section 4.1.2) for
people with knee or hand osteoarthritis. Consider topical NSAIDs and/or paracetamol ahead of
oral NSAIDs, COX-2 inhibitors or opioids. [2008]
25.Topical capsaicin should be considered as an adjunct to core treatments for knee or hand
26.Do not offer rubefacients for treating osteoarthritis. [2008]
9.3 NSAIDs and highly selective COX-2 inhibitors

Non-steroidal anti-inflammatory drugs (NSAIDs) have been available for many years and are thought
to work by reducing the production of pro-inflammatory and pain-related prostaglandins. The
discovery of different cyclooxygenase (COX) enzymes with different physiological actions brought
with it the concept that differential blockade of COX-1 (important in normal regulation of the gastro-
intestinal (GI) mucosa) and COX-2 (up-regulated at sites of inflammation amongst other functions
and thought responsible for pro-inflammatory mediator production) may provide effective
analgesic/anti-inflammatory actions without the common GI complications of traditional NSAIDs.
These GI complications are well known to clinicians and include a spectrum of problems from
dyspepsia and ulcers to life-threatening ulcer perforations and bleeds. However the blocking of COX-
2 always carried the potential for a pro-thrombotic effect, by changing the balance of pro- and anti-
thrombotic mediators.
The first novel agents to be classed COX-2 selective were rofecoxib and celecoxib, although existing
agents were also recognised for their high COX-2/COX-1 inhibitory ratios (meloxicam, etodolac). Of
these agents, rofecoxib in particular demonstrated the expected outcomes, in that initial studies
demonstrated reduced serious GI problems compared with traditional NSAIDs. Importantly, there
was no evidence to suggest that any of these agents would differ from traditional NSAIDs with
respect to efficacy. However the initial, pivotal study also demonstrated increased pro-thrombotic
cardiovascular problems (an increase in myocardial infarctions). This brought a spotlight to bear on
the cardiovascular safety of all such agents, but also on traditional NSAIDs which had varying degrees
of COX-2 selectivity. This remains a complex field because of issues including:
 Long-term toxicity must be assessed from longitudinal, observational databases with their
inherent problems, including lack of thorough assessment of an individual’s cardiovascular risk
factors
 More detailed trial data is only available on newer agents
 Drug dose in studies do not reflect usual prescribed doses or patient use
As a result of further scrutiny, there seems less reason to use the terms ‘traditional NSAIDs’ and
‘COX-2’ selective agents. It would appear that it may be more useful to return to the generic term
NSAIDs with a concomitant awareness of the differing degrees of COX-2 selectivity and different
(though not always consequent) side effect profiles.

Three questions were posed in the literature searches for this section of the guideline:
Osteoarthritis
 In adults with osteoarthritis, what are the benefits and harms of COX-2 inhibitors compared to i)
non-selective NSAIDs or ii) placebo in respect to symptoms, function and quality of life?
 In adults with osteoarthritis, what are the relative benefits and harms of i) selective COX-2
inhibitors versus nonselective NSAIDs plus GI protective agents and ii) selective COX-2 inhibitors
plus GI protective agents versus nonselective NSAIDs plus GI protective agents?
 In adults with osteoarthritis taking aspirin, what are the relative benefits and harms of selective
COX-2 inhibitors versus nonselective NSAIDs versus each of these combined with GI protective
agents?
We looked firstly at studies that focused on investigating the effects of COX-2 inhibitors compared to
non-selective NSAIDs or placebo for the outcomes of symptoms, function, quality of life, and adverse
events (AEs) where the latter where reported. Due to the high number of studies in this area only
randomised double-blinded controlled trials were considered for inclusion as evidence for all
osteoarthritis sites. However, for knee osteoarthritis studies, only double-blinded RCTs with N=400
plus participants and with a duration of longer than 4 weeks were considered for inclusion.
For the second question, we found two studies 63,405 that investigated the effects of esomeprazole
versus placebo in adults with osteoarthritis or RA receiving concomitant COX-2 inhibitors or non-
selective NSAIDs. Although these studies included a mixed osteoarthritis/RA population, it was
decided to include them, since they were the only studies reporting on the results of well-designed
RCTs on this topic. One other RCT252 was found but excluded from the evidence since it was an open-
label study and thus did not fulfil the inclusion criteria.
Finally, two studies 408,418 selected for the first question also included data on adverse gastro-
intestinal events in adults with osteoarthritis taking low-dose aspirin. They were therefore relevant
to the third question, which focuses on the relative benefits and harms of COX-2 inhibitors and non-
selective NSAIDs in adults with osteoarthritis receiving concomitant low-dose aspirin.
The relevant data is reported under the adverse events section of the evidence statements. No other
studies were identified that addressed the third question.
9.3.3 Evidence statements: COX-2 inhibitors vs placebo and NSAIDs
Summary
Symptoms: pain
Overall, the studies found that both COX-2 inhibitors were superior to placebo in terms of reducing
pain over treatment periods ranging from six weeks to six months. The majority of the data reported
here are for outcomes on the VAS and the WOMAC. The limited data on direct comparisons of COX-
2’s and non-selective NSAIDs for this outcome suggested these two drug classes were equivalent.
Only a small number of studies reported significant differences when comparing COX-2 inhibitors
with NSAIDs:
 Knee: Two studies reported in favour of celecoxib compared to naproxen (N=1061) 242; (N=1608)
514
 Knee and hip: One study reported in favour of naproxen compared with etodolac (N=76) 73.
 Mixed sites: One study reported in favour of diclofenac compared with meloxicam (N=10051) 180.
Osteoarthritis
Knee osteoarthritis
Fifteen RCTs 30,147,167,242,259,269,299,416,421,441,495,496,514 focusing on knee osteoarthritis were identified. Two

studies 434,497 were excluded due to multiple methodological limitations, including absence of
reported washout period prior to baseline assessment. All other studies were included as evidence.
The studies below reported significant reductions in pain for the following COX-2 inhibitors
compared with placebo for treatment periods ranging from 3 to 13 weeks:
 Celecoxib 100 to 400 mg (N=1003) 30; (N=1608) 147; (N=1061) 242; (N=1684) 259; (N=1551) 416;
(N=1702) 441; (N=600) 299; (N=718) 496; (N=686) 495; (N=1521) 421; (N=1082) 421; (N=599) 36; (N=608)
36
 Lumiracoxib 100 to 400 mg 147; 259; 416; 441

 Etoricoxib 5 to 90 mg (N=617) 167; (N=599) 36; (N=608) 36
 Meloxicam 7.5 or 15 mg. For the outcome pain at rest meloxicam 7.5 mg (NS) (N=513) 269
The studies below reported on outcomes for the following drug interventions for treatment period’s
ranging from 12 to 14 weeks:
 Celecoxib 100 mg resulted in significant reductions in pain compared with Naproxen 2000 mg in
WOMAC pain (p<0.001). Celecoxib 200 and 400mg and naproxen 2000 mg (NS) (N=1061) 242
 Celecoxib 100 mg and 200 mg had significant reductions in pain scores (WOMAC) compared with
naproxen 1000 mg (% change from baseline celecoxib 100mg –29.5, celecoxib 200mg –25.2
versus naproxen –21.8) (N=1003) 514
 Celecoxib 100 mg and diclofenac 50 mg (NS) (N=600) 299
 Etoricoxib 5 to 90 mg and diclofenac 150 mg (NS) (N=617) 167
 Etoricoxib 30 mg and celecoxib 200 mg (NS) (N=599 and 608) 36
 Etodolac 100 to 400 mg versus placebo joint tenderness on pressure, all measures of weight
bearing pain (standing, walking, retiring/arising, standing from chair), and night pain for
participants receiving (all p ≤ 0.05) at 12 weeks (N=36) 397
 Melixocam 15 mg and piroxicam 20 mg (NS) (N=285) 265
 Celecoxib 100 mg and dexibuprofen 400 mg (NS) (N=148) 178
Hand osteoarthritis
In favour of Lumiracoxib 200 and 400 mg compared with placebo (VAS and AUSCAN) at 4 weeks
(N=594) 172
Foot osteoarthritis
Etodolac 800 mg and naproxen 1000 mg at 5 weeks (NS) (N=60) 218 (N=60)
Knee and Hip osteoarthritis
Eleven RCTs 73,194,195,260,354,361,387,425,490,507,510 focusing on knee and hip osteoarthritis were identified.
The studies below compared the following COX-2 inhibitors with placebo, all reporting significant
reductions in pain in favour of the active drug treatment(s) for treatment period’s ranging from to 6
to 12 weeks:
 Etoricoxib 30 to 60 mg (N=501) 260; (N=528) 490
 Celecoxib 200 mg (N=356) 361
Osteoarthritis
 Meloxicam 7.5 or 15 mg (N=774) 507
The studies below reported on outcomes for the active drug comparisons for treatment periods
ranging from 6 weeks to 6 months:
 Naproxen 1000 mg (18/72) was preferred to etodolac 600 mg (7/72) for reducing pain intensity
(p=0.044). For the outcome of night pain (NS) (N=76) 73
 Etoricoxib 30 mg and ibuprofen 2400 mg (NS) (N=528) 490; etoricoxib 60 mg and diclofenac sodium
150 mg (NS) (N=516) 510 N=516)
 Meloxicam 7.5 and 15 mg and diclofenac 50 mg (NS) (N=774) 507; meloxicam 15 mg and piroxicam
20 mg (NS) (N=455) 194 ; meloxicam 7.5 mg and diclofenac sodium 100 mg (NS) (N=336) 195
 Etodolac 600 mg and tenoxicam 20 mg (NS) (N=120) 354; etodolac 600 mg and piroxicam 20 mg
(NS) (N=271) 387
 Celecoxib 200 mg and naproxen 500 mg (NS) (N=404) 425 (N=404)
Mixed sites of osteoarthritis
Three RCTs 114,180,181 included populations of adults with knee, hip, hand or spinal osteoarthritis, while
two other RCTs 408,418 included populations of adults with knee, hip or hand osteoarthritis.
The studies below reported on outcomes for the following active drug comparisons over treatment
period’s ranging from 28 days to 52 weeks:
 Diclofenac 100 mg showed a statistically significant reduction in pain on active movement (VAS)
compared to meloxicam 7.5 mg at 28 days (mean difference 2.29, 95%CI 1.38 to 3.20). For the
outcome of pain at rest (VAS) (NS) (N=10051) 180
 Lumiracoxib 400 mg, naproxen 1000mg and ibuprofen 2400 mg (NS) (N=18325) 408
 Celecoxib 200 or 400 mg compared with naproxen 1000mg and diclofenac 100mg (NS) (N=13274)
418
 Lumiracoxib 200 or 400 mg, celecoxib 200 mg and ibuprofen 2400mg (NS) (N=1042) 181
 Meloxicam 7.5 mg and piroxicam 20 mg (NS) (N= 9286) 114
Summary
Symptoms: Stiffness
Overall, the studies found that both COX-2 inhibitors were superior to placebo in terms of reducing
pain over treatment periods ranging from 15 days to six months. The majority of data reported here
are for outcomes on the WOMAC and VAS. The limited data available indicated that COX-2 inhibitors
and non-selective NSAIDs were comparable in regard to the outcome of stiffness reduction. Only a
small number of studies reported a significant difference when comparing COX-2 inhibitors with
NSAIDs:
 Knee: Two studies reported in favour of celecoxib compared to naproxen 514; (N=1061) 242
 Knee and hip: One study reported in favour of celecoxib compared to naproxen (N=404) 425.
Knee osteoarthritis
Twelve RCTs 30,147,167,242,259,299,416,421,441,495,496,514 focusing on knee osteoarthritis were identified.
The studies below all reported significant improvements in stiffness for the COX-2 inhibitors
compared with placebo for treatment period’s ranging from 6 to 13 weeks:
Osteoarthritis
 Celecoxib 100 to 400 mg (N=1003) 30; (N=1608) 147; (N=1061) 242; (N=1551) 416; (N=1702) 441;
(N=600) 299; (N=718) 496; (N=686) 495; (N=1521) 421; (N=1082)421
 Lumiracoxib 100 to 400 mg 147; (N=1684) 259; 416; 441
 Etoricoxib 5 to 90 mg (N=617) 167
 However, Celecoxib 200 mg and placebo (NS) 259
The studies below reported outcomes for the following active drug comparisons in WOMAC stiffness
for treatment periods ranging from 6 to 14 weeks:
 Celecoxib 100 mg had statistically significant reductions in stiffness scores (WOMAC) compared to
naproxen 1000 mg (% change from baseline celecoxib 100mg –25.5 versus naproxen –22.0) 514
 Celecoxib 100 mg showed significantly reductions in stiffness scores (WOMAC) compared to
naproxen (p<0.001). Celecoxib 200 and 400 mg and naproxen on this outcome (NS) (N=1061) 242
 Celecoxib 100 mg and diclofenac 50 mg (N=600) (NS) 299
Hip osteoarthritis
One RCT found that use of etodolac 100 to 400 mg resulted in significant reductions in morning
stiffness compared to placebo at 12 weeks (N=36) 397.
Celecoxib 100 mg and dexibuprofen 400 mg (NS) (N=148) 178
Hand osteoarthritis
One RCT found that at 4 weeks lumiracoxib 200mg and lumiracoxib 400mg groups both had
statistically significant improvements in pain scores (VAS, AUSCAN) compared to placebo (N=594) 172
Knee and hip osteoarthritis
Nine RCTs 73,194,195,260,387,425,490,507,510 focusing on knee and hip osteoarthritis were identified.
The studies below reported a significant difference in favour of the following COX-2 inhibitors
compared with placebo for treatment period of 12 weeks:
 Etoricoxib 30 to 60 mg (N=501) 260 (N=528); (N=528) 490
 Meloxicam 3.75 to 15 mg (N=774) 507
Out of the studies comparing two active drug comparisons, only one reported a significant reduction
in stiffness (WOMAC p=0.02) favouring celecoxib 200 mg versus naproxen 500 mg in participants
with hypertension and diabetes after 12 weeks (N=404) 425.
The remaining studies reported no statistical differences for the active drug comparisons for
treatment period’s ranging from 6 weeks to 6 months:
 Etoricoxib 30 mg and ibuprofen 2400 mg (NS) (N=528) 490; etoricoxib 60 mg and diclofenac sodium
150 mg (N=516) 510
 Meloxicam 3.75 to 15 mg and diclofenac 50 to 100 mg (NS) (N=774) 507; (N=336) 195; meloxicam 15
mg and piroxicam 20 mg (NS) (N=455) 194
 Naproxen 1000 mg and etodolac 600 mg (NS) (N=76) 73
 Etodolac 600 mg and piroxicam 20 mg (NS) (N=271) 387
Osteoarthritis
Summary: General function/global efficacy measures
Overall, it was found that both COX-2 were superior to placebo in terms of improving patient’s and
physician’s assessments of disease and overall function scores. The data on direct comparisons of
COX-2’s and non-selective NSAIDs indicate these two drug classes had similar effects for these
outcomes. Outcomes were assessed using a number of measures including the Patients’ and
Physicians’ Global Assessments and WOMAC, The treatment period’s ranged from 15 days to 52
weeks. Only a small number of studies reported a significant difference on comparisons between
two active drug interventions:
Knee: One RCT found in favour of celecoxib compared to naproxen (N=1003) 30 and one found in
favour of naproxen compared to celecoxib (N=1061) 242;
Knee osteoarthritis
Fourteen RCTs 30,36,147,167,242,259,269,299,416,421,441,495,496 focusing on knee osteoarthritis were identified.
The studies below reported in favour of the COX-2 inhibitors in comparison with placebo for
treatment period’s ranging from 3 to 13 weeks:
 Celecoxib 100 to 400 mg (N=1003) 30; (N=1608) 147 (N=1061); (N=1061) 242; (N=1684) 259; (N=1551)
416
; (N=1702) 441; (N=600) 299; (N=718) 496; (N=686) 495; (N=1082) 421; (N=1521) 421; (N=599) 36;
(N=608) 36
 Lumiracoxib 100 to 400 mg 147; 259; 416; 441
 Etoricoxib 5 to 90 mg (N=617) 167; 36;
 Meloxicam 7.5 mg and 15 mg. Outcomes of osteoarthritis Index of Severity, and Global Tolerance
of study drugs (NS) (N=513) 269
 The studies below reported on outcomes for comparisons between two or more drug
interventions for treatment period’s ranging from 12 to 14 weeks:
 Celecoxib 100 mg had a significant improvement in osteoarthritis Severity Index compared to
naproxen (p≤0.05) (N=1003) 30
 Naproxen had significantly greater improvements compared to celecoxib 100 mg and 400 mg
(p≤0.05) on the outcome of Patient’s Global Assessment, with NS differences between naproxen
and doses of celecoxib for all other measures (NS) (N=1061) 242
 Lumiracoxib 100 to 400 mg and celecoxib 200 mg (NS) (N=1608) 147; (N=1684) 259; (N=1551) 416
 Etoricoxib 5 to 90 mg and diclofenac 150mg (NS) (N=617) 167; etoricoxib 30 mg and celecoxib 200
mg (NS) (N=599) 36; (N=608) 36
 Celecoxib 100 mg and diclofenac 50 mg (NS) (N=600) 299
Hip osteoarthritis
Etodolac 100 to 400 mg resulted in significant improvements on global efficacy measures compared
to a placebo group in adults with hip osteoarthritis at 12 weeks (N=36) 397. Two other RCTs found NS
differences between COX-2 inhibitors and non-selective NSAIDs on global efficacy measures, namely
meloxicam and piroxicam (N=285) 265 and celecoxib 100 mg and dexibuprofen 400 mg (N=148) 178
Hand osteoarthritis
One RCT found that at 4 weeks lumiracoxib 200mg and lumiracocib 400mg groups both had
statistically significant improvements in Patient’s and Physician’s Global Assessments of Disease and
patient’s functional status (AUSCAN total score) compared to placebo (N=594) 172
Osteoarthritis
Nine RCTs 194,195,260,354,387,425,490,507,510 were identified that focused on knee and hip osteoarthritis.
The studies below reported significant improvements on measures of global efficacy and function
scores in favour of the following COX-2 inhibitors compared with placebo for a treatment period of
12 weeks:
 Etoricoxib 30 and 60 mg (N=501) 260; (N=528) 490
 Meloxicam 3.75 to 15 mg (N=774) 507
The following studies reported on outcomes for comparisons between the active drug comparisons
over treatment period’s ranging from 6 weeks to 6 months:
 Etoricoxib 30mg and ibuprofen 2400mg (NS) (N=528) 490
 Meloxicam 3.75 to 15 mg and diclofenac 50 mg (NS) (N=774) 507; Meloxicam 15 mg and piroxicam
20 mg (NS) (N=455) 194; meloxicam 7.5 mg and diclofenac sodium 100 mg (NS) (N=336) 195
 Celecoxib 200 mg and naproxen 500 mg (NS) assessed by participants with hypertension and
diabetes (N=404) 425
 Etodolac 600 mg and tenoxicam 20 mg (NS) (N=120) 354; etodolac 600 mg and piroxicam 20 mg
(NS) (N=271) 387; etoricoxib 60mg and diclofenac sodium 150mg (NS) (N=516) 510
two other RCTs 408,418 included populations of adults with knee, hip or hand osteoarthritis. The
treatment period’s ranged from 28 days to 52 weeks:
 Diclofenac 100 mg showed statistically significant improvements in measures of global efficacy
and function outcomes compared to meloxicam 7.5 mg at 28 days. However, these differences
did not appear to be clinically significant (NS) (N=10051) 180
 Lumiracoxib 400 mg, naproxen 1000 mg and ibuprofen 2400 mg (NS) (N=18325) 408
 Lumiracoxib 200 and 400mg, celecoxib 200 mg and ibuprofen 2400mg (NS) (N=1042) 181
 Celecoxib 200 and 400 mg and naproxen 1000mg and diclofenac 100mg (NS) (N=13274) 418
 Meloxicam 7.5 mg and piroxicam 20mg (NS) (N= 9286) 114
Summary: Physical function
Overall, both COX-2 inhibitors were superior to placebo in terms of improving physical function. In
general, data is presented for outcomes on the WOMAC. The treatment period’s ranged from 6 to
14 weeks. The limited data on direct comparisons of COX-2’s and non-selective NSAIDs for this
outcome suggested these two drug classes may be comparable for this outcome. Only two studies
reported a significant difference between active drug interventions in the knee, in favour of celecoxib
compared with naproxen (N=1003) 514; (N=1061) 242
Knee osteoarthritis
Eleven RCTs30,36,147,167,242,259,299,421,495,496,514 focusing on knee osteoarthritis The studies below reported

in favour of the following COX-2 inhibitors in comparison to placebo for treatment period’s ranging
from 6 to 12 weeks:
 Celecoxib 50 to 400 mg (N=1003) 30; (N=1061) 242; (N=600) 299 (N=600); (N=718) 496; (N=686) 495;
(N=1521) 421; (N=599) 36
Osteoarthritis

 The studies below reported on outcomes for comparisons between for the following active drug
comparisons for treatment period’s ranging from 12 to 14 weeks
 Celecoxib 100 mg had statistically significant improvements in physical function scores (WOMAC)
compared to naproxen (% change from baseline celecoxib 100 mg –26.8 versus naproxen –21.3)
(N=1003) 514
 Celecoxib 100 mg showed significantly greater improvement in WOMAC physical function
compared to naproxen (p<0.001). There was NS difference between other celecoxib dose groups
and naproxen on this outcome (N=1061) 242
; Etoricoxib 30 mg and celecoxib 200
mg (NS) (N=599) 36; (N=608) 36
 Celecoxib 100 mg and diclofenac 50 mg (NS) 299
Hip osteoarthritis
Five RCTs 260,425,490,507,510 were identified focusing on hip and knee oesteoarthritis:
The studies below reported in favour of the following COX-2 inhibitors compared to placebo on
WOMAC for a treatment period of 12 weeks:
 Meloxicam 7.5 to 15 mg (N=774) 507
The following studies reported outcomes for comparisons between the drug interventions for
treatments periods of 6 to 12 weeks:
 Etoricoxib 30 mg and ibuprofen 2400 mg (NS) (N=528) 490; and Etoricoxib 60mg and diclofenac
sodium 150mg (NS) (N=516) 510
 Meloxicam 7.5 to 15 mg and diclofenac 50 mg (NS) 507
 Celecoxib 200 mg and naproxen 500 mg in patients also with hypertension and diabetes (NS)
(N=404) 425
Physical examination findings
Hip osteoarthritis
In favour of Etodolac 100 to 400 mg compared with placebo on the outcomes of ROM hip adduction,
ROM external rotation, and ROM internal rotation (all p ≤ 0.05) at 12 weeks. Outcomes of ROM hip
abduction, walking time, and climbing stairs (NS) (N=36) 397
Foot osteoarthritis
In favour of Etodolac 800 mg compared with naproxen 1000 mg at 5 weeks on the walking up steps
(p=0.03). Outcomes of walking down stairs, chores,running errands, and walking on a flat surface
(NS) (N=60) 218
Osteoarthritis
Hip osteoarthritis
Celecoxib 100 mg and dexibuprofen 400 mg (NS) 178 (N=148)
Two RCTs found NS differences between COX-2 inhibitors and non-selective NSAIDs, meloxicam 15
mg and piroxicam 20 mg (N=455) 194 and meloxicam 7.5 mg and diclofenac sodium 100 mg (N=336)
195
in terms of quality of life outcomes as six month follow-up in adults with hip or knee
osteoarthritis.
Gastro-intestinal adverse events
Knee osteoarthritis
Fourteen RCTs 30,95,147,167,242,259,269,299,416,421,441,495,496,514 focusing on knee osteoarthritis. Statistical

significance testing of differences between treatment groups was not done. COX-2 inhibitors
generally had higher percentages of GI AEs compared to placebo, but lower percentages compared
with non-selective NSAIDs.
Two RCTs found that celecoxib 200 mg was significantly better than placebo (N=1521) 421; (N=1082)
421
(N=1082):
 Discontinuation due to lack of efficacy over 6 weeks (end of study);
 Use of rescue analgesia over 6 weeks (end of study);
 Number of patients with SAEs
Two RCTs found that there was NS difference between celecoxib 200 mg and placebo (N=1521) 421;
(N=1082):
 Number of patients with drug-related AEs;
 Number of patients with GI AEs;
 Number of patients with 1 or more clinical AE.
For the number of withdrawals due to AEs there was no significant difference for etoricoxib 30 mg
and placebo (N=599) or celecoxib 200 mg and placebo (N=599) 36; etoricoxib 30 mg and celecoxib 200
mg (NS) (N=599) 36
One study reported that etoricoxib 30 mg and celecoxib 200 mg were significantly better than
placebo for withdrawals due to AEs (N=608) 36 (N=608)
Hip osteoarthritis
Three RCTs focusing on hip osteoarthritis 178,265,397 reported on the percentages of GI AEs for COX-2
inhibitors versus non-selective NSAIDs and placebo. Statistical significance testing of differences
between treatment groups was not done. COX-2 inhibitors had higher percentages of GI AEs
compared to placebo, but lower percentages compared with non-selective NSAIDs.
Hand osteoarthritis
One RCT 172 (N=594) reported percentages of GI AEs for COX-2 inhibitors versus placebo. Statistical
significance testing of differences between treatment groups was not done. COX-2 inhibitors had
higher percentages of GI AEs compared to placebo.
Osteoarthritis
Nine RCTs 194,195,260,354,361,387,490,507,510 reported on the percentages of GI AEs for COX-2 inhibitors versus
non-selective NSAIDs and placebo. Statistical significance testing of differences between treatment
groups was not done for most studies. COX-2 inhibitors generally had higher percentages of GI AEs
compared to placebo, but lower percentages compared with non-selective NSAIDs:
Mixed
two other RCTs 408,418 included populations of adults with knee, hip or hand osteoarthritis. These
studies found that generally COX-2 inhibitors were associated with fewer GI AEs than non-selective
NSAIDs. In people not taking low-dose aspirin, COX-2 inhibitors were associated with fewer GI AEs
than non-selective NSAIDs in one study, but not in another. However, there was no difference
between the two drug classes in terms of the incidence of GI AEs for people taking low-dose aspirin.
Cardiovascular adverse events
Knee osteoarthritis
Four RCTs 95,147,269,416 focusing on knee osteoarthritis reported percentages of different cardiovascular
AEs in the table below. Statistical significance testing of differences between treatment groups was
not done. There was no visible trend in the direction of the results across the studies:
Hip osteoarthritis
One RCT focusing on hip osteoarthritis 178 reported on the percentages of cardiovascular complaints
for COX-2 inhibitors versus non-selective NSAIDs. Statistical significance testing of differences
between treatment groups was not done. COX-2 inhibitors had higher percentages of CV AEs in this
study compared with non-selective NSAIDs:
Hand osteoarthritis
One RCT 172 (N=594) reported percentages of cardiovascular AEs for COX-2 inhibitors versus placebo.
Statistical significance testing of differences between treatment groups was not done. COX-2
inhibitors had lower percentages of CV AEs in this study compared with placebo:
Four RCTs 260,387,490,510 reported percentages for CV AEs for COX-2 inhibitors versus non-selective
NSAIDs and placebo. Statistical significance testing of differences between treatment groups was not
done. COX-2 inhibitors had lower percentages of CV AEs in most of these studies compared with non-
selective NSAIDs:
One RCT 180 included populations of adults with knee, hip, hand or spinal osteoarthritis and reported
percentages of cardiac failure events without statistical significance testing. Two other RCTs 408,418
included populations of adults with knee, hip or hand osteoarthritis. One study 418 found NS
difference between COX-2 inhibitors and non-selective NSAIDs on the rate of Myocardial Infarction,
but found that non-selective NSAIDs had a higher rate of cardiac failure episodes compared with
COX-2 inhibitors. A second study 408 with a 52-week treatment and follow-up period found that COX-
Osteoarthritis
2 inhibitors and non-selective NSAIDs had similar incidences of cardiovascular AEs in adults with
osteoarthritis, regardless of concurrent use or non-use of low dose aspirin:
Renal and hepatic adverse events
Knee osteoarthritis
Four knee osteoarthritis studies reported data on renal AEs. One study 30 found that participants
receiving celecoxib had a slightly higher percentage of peripheral edema and hypertension than
participants on naproxen or placebo, and had similar percentages of participants with abnormal liver
function for each study drug. A second study 299 found that participants receiving diclofenac had
significant changes in renal values in comparison to placebo, with celecoxib having lower percentage
increases in these values than diclofenac, with most being equivalent to placebo. A third study 441
found that participants receiving celecoxib had slightly higher percentage increases in liver function
values than lumiracoxib. The fourth study 495 found NS difference between celecoxib and placebo in
terms of abnormal renal values:
Knee and hip osteoarthritis
Three studies including participants with knee and/or hip osteoarthritis reported data on renal AEs.
One study 354 reported a significant increase in urea values from baseline in the tenoxicam group,
whereas there was NS increase in these levels in the etodolac group. There were NS differences
between etodolac and tenoxicam in terms of abnormal changes in any of the other renal values
reported. A second study 387 found NS differences between etodolac and piroxicam for renal values
reported. The third study 510 found that participants receiving etoricoxib had slightly lower
percentages of peripheral edema and hypertension compared to those receiving diclofenac. A lower
percentage of participants in the etoricoxib group had abnormal increases in liver values compare to
the diclofenac group:
Three studies 114,180,408 included adults with osteoarthritis in different sites (knee, hip, hand, spine).
Two studies 114,180 found a significantly lower percentage of abnormalities in a number of renal values
for COX-2 inhibitors versus non-selective NSAIDs. The other study 408 reported no significant
difference between the two drug classes in terms of the percentages of major renal events and
serious liver abnormalities found. However, this same study found that significantly more
participants taking lumiracoxib had abnormal increases in transaminase levels compared to
participants taking NSAIDs:
9.3.4 Evidence statements: co-prescription of a proton pump inhibitor

All evidence statements in section 9.3.4 are level 1++.
Adverse events
One study 405 reported on two identically designed RCTs (VENUS N=844; PLUTO N=585) that
investigated the effect of esomeprazole 20mg or 40mg versus placebo in adults with osteoarthritis or
RA currently using either COX-2 inhibitors or non-selective NSAIDs over a period of 26 weeks.
Outcomes reported included the occurrence of gastric and duodenal ulcers and upper GI AEs.
Esomeprazole reduced the occurrence of both types of ulcer and upper GI AEs over a six-month
period in participants receiving either COX-2 inhibitors or non-selective NSAIDs in comparison to
users of these anti-inflammatory drugs who received placebo instead of a PPI:
Osteoarthritis
Table 200: Incidence of adverse events with PPI

Study Ulcer Type Placebo Esomeprazole 20mg Esomeprazole 40mg
VENUS Gastric 34/267 (12.7%) 12/267 (4.5%) 10/271 (3.7%)
Duodenal 10/267 (3.7%) 0/267 (0.0%) 0/271 (0.0%)
GU + DU 2/267 (0.7%) 0/267 (0.0%) 1/271 (0.4%)
PLUTO Gastric 19/185 (10.3%) 7/192 (3.6%) 6/196 (3.1%)
Duodenal 1/185 (0.5%) 1/192 (0.5%) 2/196 (1.0%)
GU + DU 0/185 (0%) 1/192 (0.5%) 0/196 (0.0%)
Occurrence of GI ulcers in participants receiving NSAIDs or COX-2 inhibitors
In a stratified pooled analysis of the two studies, significantly fewer participants on esomeprazole
compared with placebo developed ulcers when taking a non-selective NSAID or a COX-2 inhibitor
after 6 months of treatment.
For participants receiving non-selective NSAIDs, 17.1% (95% CI 12.6 to 21.6) of those on placebo
developed ulcers compared with 6.8% (95% CI 3.9 to 9.7, p<0.001) of those who received
esomeprazole 20 mg and 4.8% (95% CI 2.3 to 7.2, p<0.001) who received esomeprazole 40 mg.
For participants receiving COX-2 inhibitors, 16.5% (95% CI 9.7 to 23.4) of those on placebo developed
ulcers over 6 months compared with 0.9% (95% CI 0 to 2.6, p<0.001) of those who received
esomeprazole 20 mg and 4.1% (95% CI 0.6 to 7.6, p=0.002) who received esomeprazole 40 mg.
Significant reductions in ulcers occurred for COX-2 inhibitor users taking either dose of esomeprazole
in each study versus COX-2 inhibitor users taking placebo (p<0.05). For non-selective NSAID users,
esomeprazole significantly reduced ulcer occurrence in the VENUS study (p<0.001) but not in the
PLUTO study versus NSAIDs users taking placebo.
GI ulcer incidence in low-dose aspirin users
In participants taking concomitant low-dose aspirin, the ulcer incidence at 6 months was similar to
that of the whole study population for all treatment groups (placebo: 12.2%, esomeprazole 20 mg:
4.7%, esomeprazole 40 mg: 4.2%).
Serious GI AEs
Overall, there were more serious GI AEs in participants on placebo (12/452, 2.7%) than in
participants receiving esomeprazole (9/926, 1.0%) across the two studies.

We looked at studies that focused on economically evaluating nonsteroidal anti-inflammatory drugs
(NSAIDs) and COX-2 treatments, GI protective agents, or placebo for the treatment of adults with
Osteoarthritis. 61 studies (16 through cross-referencing) were identified through the literature
search as possible cost effectiveness analyses in this area. On closer inspection 56 of these studies
were excluded for:
 not directly answering the question;
 not including sufficient cost data to be considered a true economic analyses;
 involving a study population of less than 30 people;
 not including cardiovascular adverse events in the analysis.
Osteoarthritis
Five papers were found to be methodologically sound and were included as health economics
evidence. However, none of the papers were UK-based and of an acceptable standard to satisfy the
GDG as suitable evidence from which to make recommendations. For this reason this area was
outlined as important for additional economic modelling. Due to this what follows is simply a brief
review of the included studies.
One Canadian study 272 conducts a detailed cost utility analysis assessing rofecoxib and celecoxib
compared to non-selective NSAIDs. The model involved a Markov model with a decision tree within
each health state. Myocardial Infarction (MI) was included as a cardiovascular (CV) adverse event,
but no other CV adverse events were included. The model had a 5-year duration, but was limited in
that once one MI had occurred a patient could not suffer any further CV events. Direct health care
costs (in 1999 Canadian $) were calculated and QALYs were estimated using utility values obtained
by a standard gamble technique from a survey of 60 randomly selected people. The patient
population was people with OA or rheumatoid arthritis (RA) who were not prescribed aspirin. The
study assumed equal effectiveness of the drugs and only considered differences in adverse events.
The study results were as follows:

 For average-risk patients the cost per additional QALY of treating patients with rofecoxib rather
than naproxen was $455,071.
 For average-risk patients the cost per additional QALY of treating patients with diclofenac rather
than ibuprofen was $248,160, and celecoxib was dominated by diclofenac.
 For high-risk patients treatment with rofecoxib dominated treatment with naproxen + PPI. The
cost per additional QALY of treating patients with rofecoxib + PPI compared to rofecoxib on its
own was $567,820.
 For high-risk patients treatment with celecoxib dominated treatment with ibuprofen + PPI. The
cost per additional QALY of treating patients with diclofenac + PPI compared to celecoxib was
$518,339. Treating patients with celecoxib + PPI was dominated by treating patients with
diclofenac + PPI.
Hence the study concluded that treatment with COX-2 inhibitors is cost effective in high risk patient
groups with OA and RA, but not in average risk groups.
A US study considered the cost effectiveness of COX-2 inhibitors compared to non-selective NSAIDs
for people with arthritis from the Veterans Health Administration perspective 403. Two patient
groups were considered – those of any age who had a history of perforation, ulcer or bleed (PUB);
and those aged 65 years or older, regardless of their PUB history. Both these groups are regarded as
being at ‘high risk’ of a gastrointestinal (GI) event. CV events included were MI and chronic heart
failure (CHF). Costs are in 2001 US$ and QALY weights were obtained from the literature. The time
period modelled was one year, but a scenario was also included where the costs for MI were
calculated for a 10-year period. The study assumed equal effectiveness of the drugs and only
considered differences in adverse events.
The results of the study were as follows:

 The cost per additional QALY for celecoxib compared to non-selective NSAIDs was $28,214 for the
PUB history analysis. Rofecoxib was dominated by celecoxib and non-selective NSAIDs.
 The cost per additional QALY for celecoxib compared to non-selective NSAIDs was $42,036 in the
elderly patient analysis. Again rofecoxib was dominated by both celecoxib and non-selective
NSAIDs.
 Sensitivity analysis showed that with a threshold cost per QALY value of $50,000 there was an
88% probability that celecoxib would be cost effective in the elderly population, and a 94%
probability that it would be cost effective in the PUB history population.
Osteoarthritis
Another US study 427 conducted a cost utility analysis comparing COX-2 inhibitors to nonselective
NSAIDs. The patient population was 60-year-old patients with OA or RA who were not taking aspirin
and who required long-term NSAID therapy for moderate to severe arthritis pain. A lifetime duration
was adopted. CV events were included in sensitivity analysis. Patients with a history of ulcer
complications were included in sensitivity analysis. A third party payer perspective was adopted for
costs (estimated in 2002 US$) and utility values validated by previous investigators were used to
allow QALYs to be calculated. The study assumed equal effectiveness of the drugs and only
considered differences in adverse events.

 The cost per additional QALY of treating patients with a COX-2 inhibitor (celecoxib or rofecoxib)
rather than naproxen was $395,324.
 The cost per additional QALY of treating patients with a COX-2 inhibitor rather than naproxen
assuming a high-risk cohort was $55,803.
A UK study conducted a cost minimisation analysis based on patients aged 18 or over with acute
osteoarthritis of the hip, knee, hand or vertebral spine, taking an NHS perspective 443. The
treatments considered were meloxicam, diclofenac, and piroxicam, and all resource use associated
with GI and non-GI adverse events were included as costs, calculated in 1998£. However, the
duration of the model was only 4 weeks, giving little time for costs to be accrued.

 Cost per patient was least for meloxicam (£30), followed by piroxicam (£35) and diclofenac (£51).
An Australian conducts a cost utility analysis on a number of different interventions for OA 413. One
of these analyses involved comparing diclofenac and naproxen with celecoxib. Efficacy was included
in the analysis by allocating QALY gains due to pain relief. PUBs and CHF were included as adverse
events. Health service costs were considered and are calculated in 2000-2001 Aus$, and QALYs were
calculated using the transfer to utility (TTU) technique. The drugs were compared to placebo. The
analysis is based on 12 months of treatment. A significant problem with the study is that QALY
scores for non-fatal AEs are not incorporated into the modelling, meaning that only fatal AEs are
reflected in the results.

 The best estimate of cost per additional QALY of treating patients with naproxen rather than
placebo (paracetamol) was $7,900 per additional QALY, incorporating a 5% discount rate.
 The best estimate of cost per additional QALY of treating patients with diclofenac rather than
 The best estimate of cost per additional QALY of treating patients with celecoxib rather than
 The study does not directly compare non-selective NSAIDs to COX-2 inhibitors, but the results
suggest that net utility gains are similar for the two types of drugs, while non-selective NSAIDs
result in lower costs.
9.3.6 Health economic modelling (CG59)

We conducted a cost-effectiveness analysis, comparing paracetamol, standard NSAIDs and COX-2
inhibitors at doses relevant to clinical practice for which there was robust clinical trial data sufficient
to draw reliable conclusions: paracetamol 3000mg, diclofenac 100mg, naproxen 750mg, ibuprofen
1200mg, celecoxib 200mg, etoricoxib 60mg and lumiracoxib 100mg. We also tested the cost-
effectiveness of adding omeprazole, a proton pump inhibitor, to each of these NSAIDs/COX-2
Osteoarthritis
inhibitors. It should be noted that we did not consider the cost-effectiveness of other NSAIDs,
meloxicam or etodolac, due to lack of suitable data.
The analysis was based on an assumption that the NSAIDs and COX-2 inhibitors are equally effective
at controlling OA symptoms, but that they differ in terms of GI and CV risks. The adverse event risks
were taken from three key studies: MEDAL, CLASS and TARGET. As the doses of both standard
NSAIDs and COX-2 inhibitors were very high in these trials, we adjusted the observed rates to
estimate the impact of more commonly-used and licensed doses. The effectiveness of NSAIDs/COX-2
inhibitors and paracetamol at controlling OA symptoms was estimated from a meta-analysis of RCTs.
Given these assumptions, lower doses of a drug will always be more cost-effective than a higher dose
of the same drug. In practice, though, some individuals may require higher doses than we have
assumed in order to achieve an adequate therapeutic response.
One clear result of our analysis is that it is cost-effective to add a generic PPI to standard NSAIDs and
COX-2 inhibitors. We did not test the relative cost-effectiveness of other gastroprotective agents,
because of the superior effectiveness evidence for PPIs, and the currently very low cost of
omeprazole at this dose.
Given our assumptions and current drug costs, Celecoxib 200mg is the most cost-effective of the
included NSAIDs/COX-2 inhibitors. This result was not sensitive to the assumed duration of
treatment (from 3 months to 2 years), or to the baseline risk of GI events in the population (55 years
vs 65 years). It was also relatively insensitive to the baseline risk of CV events. In patients who
cannot tolerate celecoxib, lumiracoxib 100mg would be a cost-effective alternative (see below for
information on liver toxicity). Etoricoxib 30mg is not currently available but there are some trial data
on efficacy and safety. As part of the sensitivity analyses, it is also a cost-effective alternative if its
adverse event rates are extrapolated from 60mg data, depending on the price. The relative cost-
effectiveness of these two options in this context depends primarily on their cost.
However, it is important to note substantial uncertainties over the relative rates of adverse events
associated with the COX-2 drugs estimated from the MEDAL, TARGET and CLASS studies. In
particular, the estimated risk of stroke for celecoxib from CLASS was surprisingly low. If this is an
underestimate, then lumiracoxib 100mg or etoricoxib 30mg could be more cost-effective than
celecoxib 200mg. The full data submitted to the American Food and Drug Administration were used
for the economic model.
Observational data implies a less attractive cost-effectiveness ratio for celecoxib (around £30,000 per
QALY), though this estimate may be biased by its use in selected higher-risk patients in clinical
practice. There was no observational data for the other COX-2 inhibitors.
For patients who cannot, or do not wish to, take a COX-2, the relative cost-effectiveness of
paracetamol and standard NSAIDs depends on their individual risk profile, as well as the dose
required to achieve an adequate therapeutic response:
• With low GI and CV risk (patients aged under 65 with no risk factors), standard NSAIDs with a
PPI do appear to be relatively cost-effective in comparison with paracetamol or no intervention.
• For patients with raised GI or CV risk (aged over 65 or with risk factors), standard NSAIDs are
not a cost-effective alternative to paracetamol. In our model, the risks of these treatments
outweighed the benefits of improved control of OA symptoms, as well as incurring additional costs
for the health service.
The model provides cost-effectiveness estimates at a population level, including for NSAIDs in people
with increased GI risk. Clearly, for many of these people NSAIDs will be contra-indicated and thus the
average cost-effectiveness in those who remain eligible will be better than the estimate given here.
Osteoarthritis
The relative cost-effectiveness of particular NSAIDs and COX-2 inhibitors will vary depending on
individual patients' GI and CV risk factors.
The model assesses which of the drugs is most suitable as the first choice for treatment. In instances
where the drug is not tolerated or gives inadequate relief, and a different drug from this class is
sought as the second choice, treatment needs to be carefully tailored to the individual and it is not
possible to provide useful recommendations in a national clinical guideline for this.
The relative costs of the standard NSAIDs employed in this model (diclofenac 100mg, naproxen
750mg and ibuprofen 1200mg) prescribed concurrently with a PPI are similar, and uncertainties over
the relative incidence of adverse events with these drugs make it difficult to draw clear conclusions
about their comparative cost-effectiveness.
The doses and costs considered in the model are shown in Appendix D. Because the incremental
cost-effectiveness ratios (ICERs) are affected by dose and individual risk factors, the Guideline
Development Group felt it would be unwise to single out specific drugs and doses within these
classes, except for etoricoxib 60mg, which was consistently dominated (more expensive and has
overall lower gain in QALYs than comparator drugs) in the model results. Readers should be alert to
changes in available drug doses and costs after this guideline is published.

A large amount of clinical trial evidence supports the efficacy of both traditional NSAIDs and COX-2
selective agents in reducing the pain and stiffness of osteoarthritis with the majority of studies
reflecting short-term usage and involving knee or hip joint osteoarthritis. There is no strong evidence
to suggest a consistent benefit over paracetamol, although some patients may obtain greater
symptom relief from NSAIDs. There are again no data to suggest benefits above opioids, but there is
a lack of well-designed comparator studies.
The GDG would like to draw attention to the findings of the evidence review on the efficacy of
Update 2014
paracetamol that was presented in the consultation version of the guideline. That review identified
reduced efficacy of paracetamol in the management of osteoarthritis compared with what was
previously thought. The GDG believes that this information should be taken into account in routine
prescribing practice until the planned full review of evidence on the pharmacological management of
osteoarthritis is published (see the introduction to this guideline and the NICE website for further
details).
All NSAIDs, irrespective of COX-1 and COX-2 selectivity are associated with significant morbidity and
mortality due to adverse effects on the GI, renal and cardiovascular system. It should be noted again
that clinical trials recruit patients without the serious co-morbidities that would be present in routine
clinical practice and that supra-normal doses of newer agents are commonly used in clinical trials in
order to demonstrate safety.
GI toxicity
There are some data to support that certain COX-2 selective agents reduce the incidence of serious
GI adverse events (such as perforations, ulcers and bleeds) when compared to less selective agents,
while the evidence for other agents has been more controversial. Dyspepsia, one of the commonest
reasons for discontinuation, remains a problem with all NSAIDs irrespective of COX-2 selectivity.
Osteoarthritis
Liver toxicity
At the time of writing, concerns have been raised about liver toxicity associated with high doses of
lumiracoxib. In the absence of long-term data applicable to all drugs in this class, it was not possible
to include this in the economic model, though the cost of liver function tests was added, in line with
the manufacturer and MHRA's recommendations at the time of writing. The model therefore
represents the current situation regarding liver toxicity. The GDG were aware that further data will
emerge in the lifetime of this guideline and therefore did not specify lumiracoxib in the
recommendations. As with all NICE guidelines, prescribers should be aware of the Summaries of
Product Characteristics.
Cardiovascular toxicity
All NSAIDs have the propensity to cause fluid retention and to aggravate hypertension, although for
certain agents this effect appears to be larger (etoricoxib) and for others it appears smaller
(lumiracoxib). Increasingly a pro-thrombotic risk (including myocardial infarction and stroke) has
been identified with COX-2 selective agents in long-term studies, and there does seem to be some
evidence for a dose effect. These observational studies also demonstrate an increased cardiovascular
risk from older agents such as diclofenac which has high COX-2 selectivity. It is possible that naproxen
does not increase pro-thrombotic risk. All NSAIDs may antagonise the cardio-protective effects of
aspirin.
Summary
All potential adverse effects must be put in perspective of patient need and individual risk including
the influence of the patient’s age on their GI risk. Best estimates of toxicity data, along with the
uncertainty in these values, are detailed in Appendix D. The recommendations mention assessment
and monitoring of risk factors, but are unable to specify these because of the rapidly emerging
evidence base in this area. Prescribers will be informed by the regularly updated Summaries of
Product Characteristics.
There is likely to be a continuing role for NSAIDs/COX-2 inhibitors in the management of some
patients with OA. Allowing for the inevitable differences in individual patient response, in general the
choice between NSAIDs and COX-2 inhibitors is influenced by their separate side-effect profiles,
which tend to favour COX-2 inhibitors, and cost, which tends to favour NSAIDs. Extensive sensitivity
analyses showed that these are the two factors which most strongly influence the results of the
economic model.
Given that costs are constantly changing and that new data on adverse events will become available,
the GDG deemed it unwise to suggest a particular ranking of individual drugs. Indeed, there is no
clear distinction between the two sub-classes. Meloxicam and etodolac were not included in the
model because of a lack of comparable trial data, and other NSAIDs were excluded because of the
rarity of use in the UK, according to the Prescription Pricing Authority (see Appendix D for details). It
is beyond the role of a clinical guideline to attempt to categorise meloxicam or etodolac into one of
the two sub-classes. It is however, worth noting that each of the drugs in this section varies in its
COX-1 / COX-2 selectivity.
There was a consistent difference between etoricoxib 60mg and the other drugs in the model, and
therefore in line with the original aim of the economic model, advice is given against the use of
etoricoxib 60mg as the first choice for treatment.
The GDG also noted that the incidence of potentially serious upper GI problems can be reduced by
the use of PPIs, and the potential benefit of co-prescription of PPIs was an important element of the
Osteoarthritis
cost-effectiveness analysis. In fact, the analysis found that it was always more cost-effective to co-
prescribe a PPI than not to do so. The primary paper discussed was the Scheiman paper405. The Lai
paper was excluded as it was an open-label trial and the Chan paper63 had several limitations: i) a
population following hospitalisation for upper GI bleeding (which was not what we were looking at
for the model); and ii) it had a zero event rate in the PPI arm of the trial. This meant that we were
unable to calculate a relative risk, which is required for the model. Hence the Chan paper
corroborates the effectiveness of adding a PPI to a COX-2, but has not been used for the sensitivity
analysis. The GDG have attempted to balance all these factors in the following recommendations.
Although NSAIDs and COX-2 inhibitors may be regarded as a single drug class of "NSAIDs", these
recommendations use the two terms for clarity and because of the differences in side-effect profile.
27.Where paracetamol or topical NSAIDs are ineffective for pain relief for people with
osteoarthritis, then substitution with an oral NSAID / COX-2 inhibitor should be considered.
[2008]
28.Where paracetamol or topical NSAIDs provide insufficient pain relief for people with
osteoarthritis, then the addition of an oral NSAID / COX-2 inhibitor to paracetamol should be
considered. [2008]
29.Use oral NSAIDs / COX-2 inhibitors at the lowest effective dose for the shortest possible period
of time. [2008]
30.When offering treatment with an oral NSAID / COX-2 inhibitor, the first choice should be either
a standard NSAID or a COX-2 inhibitor (other than etoricoxib 60mg). In either case, co-prescribe
with a proton pump inhibitor (PPI), choosing the one with the lowest acquisition cost. [2008]
31.All oral NSAIDs / COX-2 inhibitors have analgesic effects of a similar magnitude but vary in their
potential gastrointestinal, liver and cardio-renal toxicity; therefore, when choosing the agent
and dose, take into account individual patient risk factors, including age. When prescribing
these drugs, consideration should be given to appropriate assessment and/or ongoing
monitoring of these risk factors. [2008]
32.If a person with osteoarthritis needs to take low-dose aspirin, healthcare professionals should
consider other analgesics before substituting or adding an NSAID or COX-2 inhibitor (with a PPI)
if pain relief is ineffective or insufficient. [2008]
Osteoarthritis
Intra-articular Injections
10 Intra-articular Injections
10.1 Introduction
Corticosteroids
Corticosteroid injections are used to deliver high doses of synthetic corticosteroids to a specific joint,
while minimising systemic side effects. Corticosteroids have marked anti-inflammatory effects, and it
is assumed that their analgesic action in osteoarthritis is in some way related to their anti-
inflammatory properties. Certainly intra-articular corticosteroids can reduce the volume of synovitis
of osteoarthritis338, however the relationship between osteoarthritis synovitis and pain is less clear. It
is recognised that clinical examination is not sensitive in detecting inflammation (synovial
hypertrophy or effusions) when compared with imaging methods such as ultrasonography or MRI97,
so clinical prediction of response to a corticosteroid injection is unreliable. The presence of an
effusion is not in itself an indication for corticosteroid injection, unless there is significant restriction
of function associated with the swelling. Rather, the indication should be based on severity of pain
and disability.
Hyaluronans
Endogenous hyaluronan (HA, previously known as hyaluronic acid) is a large, linear

glycosaminoglycan and is a major non-structural component of both the synovial and cartilage
extracellular matrix. It is also found in synovial fluid and is produced by the lining layer cells of the
joint. HA is removed from the joint via the lymphatic circulation and degraded by hepatic endothelial
cells. Its key functions in the joint are to confer viscoelasticity, lubrication and help maintain tissue
hydration and protein homeostasis by preventing large fluid movements and by acting as an osmotic
buffer. Synthetic HA was isolated from roosters’ comb and umbilical cord tissue and developed for
clinical use in ophthalmic surgery and arthritis in the 1960s. The beneficial effects in ophthalmic
surgery were followed by the use of HA in osteoarthritis: the rationale was to replace the properties
lost by reduced HA production and quality as occurs in osteoarthritis joints, a concept known as
Update 2014
viscosupplementation. Commercial preparations of HA have the same structure as endogenous HA
although cross-linked HA molecules (known as hylans) were later engineered by linking HA molecules
in order to obtain greater elasto-viscosity and intra-articular dwell-time. However, the mechanism by
which HA exerts its therapeutic effect, if any, is not certain, and evidence for restoration of
rheological properties is lacking. It has been suggested that two stages might be involved; an initial
biomechanical stage followed by a physiological stage. It is suggested that biomechanical
mechanisms initially come into effect when the synovial fluid in the osteoarthritic joint is replaced by
the higher molecular weight exogenous HA. Clinical studies report that exogenous HA is able to assist
in restoring the elastoviscosity, and the lubricating and shock absorbing abilities, of synovial fluid. It is
noted that physiological mechanisms may account for the clinical benefits of intra-articular
administration of HA that persist beyond the residence time of HA, although evidence has largely
been obtained from preclinical studies. Given the relatively short intra-articular residency (hours to
days), any hypothesis for its mechanism of action must account for the sometime reported long-
duration of clinical efficacy (months). CG 59 did not recommend the use of intra-articular hyaluronan
injections. This update has prioritised a review of evidence published since CG59.
10.1.1 Methodological introduction: corticosteroids

We looked for studies that investigated the efficacy and safety of intra-articular injection of
corticosteroid compared with placebo with respect to symptoms, function and quality of life in adults
Osteoarthritis
with osteoarthritis. One Cochrane systematic review and meta-analysis on knee osteoarthritis
patients 26 and 3 additional RCTs on osteoarthritis of the hip146 368,368 or thumb 301 were found. No
relevant cohort or case-control studies were found.
The meta-analysis assessed the RCTs for quality and pooled together all data for the outcomes of
symptoms, function and AEs. However, the outcome of quality of life was not reported. The results
for quality of life have therefore been taken from the individual RCTs included in the systematic
review.
The meta-analysis included 12 RCTs (with N=653 participants) on comparisons between intra-
articular corticosteroids and intra-articular placebo injections in patients with knee osteoarthritis.
Studies included in the analysis differed with respect to:
 Type of corticosteroid used (1 RCT prednisolone acetate; 4 RCTs triamcinolone hexacetonide; 1
RCT methylprednisolone; 3 RCTs hydrocortisone solution; 2 RCTs triamcinolone acetonide; 1 RCT
cortivazol; 1 RCT methylprednisolone acetate)
 Treatment regimens
 Trial design, size and length.
Tests for heterogeneity were performed for any pooled results, but no evidence of heterogeneity
was found between studies that were combined. Unless otherwise stated, all evidence statements
are derived from data presented in the systematic review and meta-analysis.
The three additional RCTs focused on the outcomes of symptoms, function and quality of life. The
three included RCTs were similar in terms of osteoarthritis diagnosis (radiologically).
However, they differed with respect to osteoarthritis site, corticosteroid agent, and sample size.
10.1.2 Evidence statements: Intraarticular (IA) corticosteroids vs placebo
Knee
Overall, the evidence appraised by the Cochrane review suggests a short-term benefit (up to one
week) in terms of pain reduction and patient global assessment after IA injections with
corticosteroids in the knee. Beyond this period of time there were non-significant differences
between IA corticosteroids and IA placebo as reported by most of the studies identified.
There was evidence of pain reduction between two weeks to three weeks but a lack of evidence for
efficacy in functional improvement.
No significant differences between corticosteroids and placebo were reported at any time point by
studies evaluating the following outcomes in patients with knee OA:
 functional improvement (e.g. walking distance, range of motion)
 Stiffness
 quality of life
 safety
 study withdrawals.
Hip and Thumb
No conclusive results were observed in studies evaluating IA injections of corticosteroids and placebo
in other joints affected by OA (i.e. hip and thumb).
Osteoarthritis
Table 201: Pain in knee OA

Knee Assessment
26
Number of knees MA , 1 RCT Hydrocortisone 2 weeks post- RR 1.81, 95%CI 1.09 to
improved (pain) (N=71) tertiary-butylacetate injection 3.00, p=0.02, NNT=3)
vs placebo
Favours CS
26
30% decrease in VAS MA , 1 RCT Cortivazol vs placebo 1 week post- RR 2.56, 95%CI 1.26 to
pain from baseline (N=53) vs placebo injection 5.18, p=0.009
Favours CS
26
15% decrease in VAS MA , 1 RCT Methylprednisolone 3 weeks post- RR 3.11, 95%CI 1.61 to
pain from baseline (N=118) vs placebo injection 6.01, p=0.0007
Favours CS
26
Pain (VAS) MA , 3 RCTs Cortivazol vs placebo 1 week post- WMD –21.91, 95%CI –
(N=161) injection 29.93 to –13.89,
p<0.00001
Favours CS
26
Pain (VAS) MA , 1 RCT Cortivazol vs placebo 12 weeks WMD –14.20, 95%CI –
(N=53) post-injection 27.44 to –0.96, p=0.04
Favours CS
26
WOMAC pain MA , 1 RCT Triamcinolone 1 year post- WMD –13.80, 95% CI –
(N=66) acetonide vs placebo injection 26.79 to –0.81; p=0.04
Favours CS
Table 202: Global assessment in knee OA

Knee Assessment
Global assessment Reference Intervention time Outcome / Effect size
26
Patients global MA , 3 RCTs CS vs placebo Range: 1 to RR 2.22, 95%CI 1.57 to
assessment (number of (N=190) 104 weeks 3.15, p<0.00001
patients preferring
treatment Favours CS
26
Overall improvement MA , 3 RCTs CS vs placebo Range: 1 to RR 1.44, 95%CI, 1.13 to
(N=156) 104 weeks 1.82; p=0.003
Favours CS
Table 203: Pain in hip OA

Hip Assessment
146
Percentage of patients 1 RCT Bupivacaine + 1 month post- Improvement: 75% (CS)
with improved pain (N=30) triamcinolone vs injection and 64% (placebo)
relief placebo.
Osteoarthritis
Hip Assessment
146
Percentage of patients 1 RCT Bupivacaine + 1 and 3 1 month: 8% (CS) and
whose pain relief was (N=30) triamcinolone vs months post- 27% (placebo)
unchanged placebo. injection 3 months: 17% (CS) and
36% (placebo)
146
Percentage of patients 1 RCT Bupivacaine + 1 and 3 1 month: 17% (CS) and
whose pain had (N=30) triamcinolone vs months post- 9% (placebo)
worsened placebo. injection 3 months: 50% (CS) and
8.5% (placebo)
146
Percentage of patients 1 RCT Bupivacaine + 3 months and 3 months: 33% (CS) and
with improved pain (N=30) triamcinolone vs 12 months 55% (placebo)
relief at follow-up placebo. post-injection 12 months: 8% (CS) and
18% (placebo)
368,368
Pain on walking 1 RCT Methylprednisolone 14 and 28 Over 3 months: SMD
(N=104) vs placebo days and over steroid = 0.6, 95% CI 0.1
the 3 month to 1.1, p=0.021
treatment 14 and 28 days: both
period p=0.006
FAVOURS CS
Table 204: Pain in thumb OA

Thumb (CMC) Assessment
301
Pain (VAS, mm) change 1 RCT Triamcinolone vs 12 weeks and 12 weeks: 3.5 (CS) and
from baseline (N=40) placebo 24 weeks 23.3 (placebo)
post-injection 24 weeks: 0.0 (CS) and
14.0 (placebo)
301
Joint tenderness (scale 1 RCT Triamcinolone vs 12 weeks and 12 weeks: 0.5 (CS) and
0-3) change from (N=40) placebo 24 weeks 2.0 (placebo) 24 weeks:
baseline post-injection 0.5 (CS) 2.5 (placebo)
Table 205: Function in hip OA

Hip Assessment
368,368
OARSI outcome 1 RCT Methylprednisolone Day 14 and Day 14: 56% (CS) and
measures (N=104) vs placebo day 28 (end of 33% (placebo)
treatment) Day 28: 66% (CS) and
44% (placebo)
Table 206: Global assessment in hip OA

Hip
368,368
Patient’s global 1 RCT Methylprednisolone 14 days, 28 NS
assessment (N=104) vs placebo days and 3
months (end
of study)
Osteoarthritis
Table 207: Global assessment in thumb OA

Thumb (CMC)
301
Physician’s global 1 RCT Triamcinolone vs 12 weeks and 12 weeks: 0.5 (CS) and
assessment (N=40) placebo 24 weeks 2.3 (placebo)
5.0 (placebo)
301
Patient’s global 1 RCT Triamcinolone vs 12 weeks and 12 weeks: 0.0 (CS) and
assessment (N=40) placebo 24 weeks 2.3 (placebo)
5.0 (placebo)
Table 208: Adverse events in hip OA

Hip
Adverse events Assessment
368,368
SAEs or infection 1 RCT Methylprednisolone Over 3 None for either group
(N=104) vs placebo months study
Table 209: Total withdrawals in thumb OA

Thumb (CMC) Assessment
Total withdrawals Reference Intervention time Outcome / Effect size
301
Number of withdrawals 1 RCT Triamcinolone vs Over 24 weeks Both N=3
(N=40) placebo study
Corticosteroids
Generally the research evidence demonstrates that intra-articular corticosteroid injections provide
short-term (1-4 weeks) reduction in osteoarthritis pain, although effects on function appear less
marked. The effects have been best demonstrated for knee osteoarthritis, although there are some
data for efficacy in hip and hand osteoarthritis. The GDG noted that these injections are widely used
in many osteoarthritis sites. There is no clear message from this evidence on whether any particular
corticosteroid preparation is more effective than another, or on which dose of a given preparation is
most effective. In clinical practice, the short-term pain relief may settle flares of pain and also allow
time for patients to begin other interventions such as joint-related muscle strengthening.
The risks associated with intra-articular corticosteroid injection are generally small. A small
percentage of patients may experience a transient increase in pain following injection. Subcutaneous
deposition of steroid may lead to local fat atrophy and cosmetic defect. Care should always be taken
when injecting small joints (such as finger joints) to avoid traumatising local nerves. There is a very
small risk of infection. The question of steroid-arthropathy, that is, whether intra-articular steroids
may increase cartilage loss, remains controversial and is currently based on animal model and
retrospective human studies. Nevertheless, caution should be applied if injecting an individual joint
on multiple occasions and other osteoarthritis therapies should be optimised
Osteoarthritis
33.Intra-articular corticosteroid injections should be considered as an adjunct to core treatments

for the relief of moderate to severe pain in people with osteoarthritis. [2008]
10.2 Intra-articular injections of hyaluronic acid/ hyaluronans in the

management of OA in the knee, hand, ankle, big toe and hip.
10.2.1 What is the clinical and cost effectiveness of intra-articular injections of hyaluronic acid/
hyaluronans in the management of OA in the knee, hand, ankle, big toe and hip?

Intervention/s Adant
Arthrum H
Artz (Artzal, Supartz)
Biohy (Arthrease, Euflexxa, Nuflexxa)
Durolane (NASHA - non-animal stabilized hyaluronic acid)
Fermathron
Go-On
Hyalart
Hyalgan
Update 2014
Hylan G-F 20 (Synvisc and Synvisc one)
Hyruan
NRD-101 (Suvenyl)
Orthovisc
Ostenil
RenehaVis
Replasyn
SLM-10
Suplasyn
Supartz
Synject
Synocrom
Synopsis
Viscoseal
Zeel compositum
Hyaluronan (brand name not identified)
Comparison/s Placebo
Usual treatment
Steroid injection (including for example methylprednisolone acetate, triamcinolone
hexacetonide and betamethasone)
Another hyaluronan
Osteoarthritis
Outcomes Short-term outcome will be defined as the measurement point less than or equal to 13
weeks post injection. The longer-term outcome will be defined as the measurement
point of more than 13 weeks post injection. If two follow-up assessments were
completed within one of the defined time points the results of the later of the two
assessments were selected for inclusion.
Global joint pain (VAS or NRS, WOMAC pain subscale, WOMAC for knee and hip only,
AUSCAN for hand)
Function (WOMAC function subscale for hip or knee or equivalent such as AUSCAN
function subscale and change from baseline)
Stiffness (WOMAC stiffness score change from baseline)
Time to joint replacement
Minimum joint space width
Quality of life (EQ5D, SF 36)
Patient global assessment
OARSI responder criteria
Adverse events
-post injection flare
Study design RCTs, systematic reviews and meta-analyses
Update 2014
Due to the volume of evidence pertaining to hyaluronan intra-articular injections evidence
statements are only presented for the outcomes predefined as critical by the GDG i.e pain, adverse
events and quality of life. The full forest plots can be found in appendix I.5. The GDG noted that any
degree of structure modification should be taken as clinically important, thus the MID chosen for
structural modification outcomes was the line of no effect or zero.
OA Knee
One Cochrane review which included 76 studies 27 comparing hyaluronans to placebo or active
treatment in knee osteoarthritis was identified. In addition, 20 studies that were published after the
Cochrane review were also identified6,12,31,72,84,117,200,210,225,234,248,257,270,328,346,356,357,417,419,420. Evidence
from these are summarised in the clinical GRADE evidence profiles below. See also the study
 The protocol for this evidence review (see Appendix C) differed slightly from the protocol for the
Cochrane review 27. Any differences were agreed with the GDG. Due to this, we have excluded
some papers that were included in the Cochrane review17,25,118,170,199,230,374,506 . The reasons for
exclusion are fully listed in Appendix J.
 This review included all hyaluronan products, including those that are licensed and unlicensed for
use in the UK, as requested by NICE
 The comparisons reported in this review include placebo (saline) injections, NSAIDs, steroid
injections, physiotherapy, exercise, conventional or appropriate care. There were eleven studies
that compared one HA product to another and two studies that compared different numbers of
injections of the same HA product .
 The doses and treatment schedules used in the studies varied (see evidence tables, Appendix G).
 No studies included in this review reported time to joint replacement
Osteoarthritis
 One study published after the Cochrane review was included but could not be analysed because it
did not report data in a form that could be extracted356 (see Appendix G)
 Where more than one result was reported for a time point the latest result was used. The only
study where this was different was for Petrella (2006), who reported results at 6 and 12 weeks;
results from week 6 were used in the meta-analysis because the 12 weeks results could not be
used.
 A fixed effects model was used for analysis unless there was significant heterogeneity which was
unexplained by subgroup analysis, in which case a random effects model was used.
OA Hip
 Five studies were identified which evaluated the use of hyaluronans in osteoarthritis of the hip.
Four of these studies included licensed preparations 16,16,368,428,449 and one study looked at
unlicensed preparations 383.
 The comparisons included placebo (saline injections) and steroid injections.
 One study reported data for efficacy measures in graphs and only adverse event data was
extracted from this study for analysis 16.
 None of the studies reported mean/ minimum joint space width or time to joint replacement.
OA Ankle
 Six studies were identified which evaluated the use of hyaluronans in osteoarthritis of the ankle.
Three of these studies included licensed preparations 82,396,500 and two studies used unlicensed
preparations 108,232.
 The doses and treatment schedules used in the studies varied (see evidence tables, Appendix
G).One study compared different doses and treatment schedules for the same hyaluronan
(Orthovisc), but the efficacy measures were reported as medians and could not be included in the
analysis. Only adverse event data was extracted from this study 500.
Update 2014
 One study reported data for efficacy measures as percentage change from baseline in graphs.
Data for only adverse events was extracted from this study 82. Another study also reported data
for responder rate in graphs and this was not extracted or analysed 396.
 None of the studies reported mean/ minimum joint space width or time to joint replacement.
OA Base of thumb
 Four studies were identified which evaluated the use of hyaluronans in osteoarthritis of the
trapezio-metacarpal joint. All studies included licensed preparations 18
 One study reported the Mann-Whitney test scores for its efficacy measures and not the actual
results, hence was not included in the analysis 156. Another study was an open label study 18.
 None of the studies reported WOMAC pain, WOMA function, WOMAC stiffness, mean/ minimum
joint space width or time to joint replacement.
OA Great toe
 Two studies were identified which evaluated the use of hyaluronans in osteoarthritis of the first
metatarsophalangeal joint. Both included licensed preparations 320,364.
Osteoarthritis
 Both studies compared single injections of hyaluronans. However, the products used were
different and one study compared hyaluronan to saline injection 320 whereas the second study
compared it to triamcinolone acetonide 364.
 Neither study reported WOMAC pain, WOMAC function, WOMAC stiffness, mean/minimum joint
space width or time to joint replacement.

OA Knee
Altman 2009 EUFLEXXA vs saline People with  WOMAC pain
Knee OA  QoL
Arensi 2006 Go-on vs Hyalgan People with  WOMAC pain, function
Knee OA & stiffness
 Patient global
assessment
 Adverse events
Bellamy 2009 HA +/- other treatment vs 76 studies in
placebo and/or other people with
active treatment or Knee OA
different HA or different
number of injections of
same HA
Berenbaum Go-on vs Hyalgan People with  WOMAC pain
2012 knee OA  OMERACT-OARSI
Update 2014
responders
Chevalier 2010 Hylan GF20 (licensed People with  WOMAC pain

product) vs placebo knee OA  WOMAC function
Conrozier 2009 Different number of people with Adverse events Cannot
injections/ volumes of Knee OA extract data
Hylan GF 20 for WOMAC
and VAS
pain
outcomes
Diracoglu 2009 Hylan GF20 vs placebo People with  WOMAC pain, function
Knee OA & stiffness
 VAS pain rest
 VAS pain activity
Huang 2011 Hyalgan vs placebo  People with  WOMAC pain, function

Knee OA & stiffness
 VAS pain
 Patient global
assessment
 Adverse events
Iannitti 2012 Synvisc vs Vanofill People  Pain (VAS) Data
with knee  WOMAC pain, stiffness presented as
OA and function SEM,
converted to
Osteoarthritis

SD by NCGC
Jorgensen 2010 Hyalgan vs placebo  People with  Vas pain
Knee OA  Patient global
assessment
 QoL
 Adverse events
Kawasaki 2009 Artz vs exercise  People with 
Knee OA
Kulpanza 2010 Orthovisc vs placebo People with  WOMAC pain, function
Knee OA & stiffness
 Vas spontaneous
 VAS night
 VAS motion
Patient global assessment
Lee 2006 Hyruan vs Hyal People with  VAS pain (weight
Knee OA bearing
 WOMAC (data in graphs
only)
 Adverse events
Lundsgaard Hyalgan vs placebo People with  VAS pain-rest
2008 Knee OA  VAS pain- night
Update 2014
 VAS pain- movement
 Patient global
assessment
Navarro – Adant vs placebo People with  OARSI responder criteria
Sarabia 2011 Knee OA  WOMAC pain, function
& stiffness?
 Patient global
assessment
Pavelka 2011 Sinovial vs Hylan GF 20 People with 
Knee OA
Petrella 2006 HA (no product specified): People with  WOMAC pain, function
6 injections vs 3 injections Knee OA & stiffness
 VAS pain walking
 VAS pain stepping
 Patient global
assessment
 SF36
 Adverse events
Petrella 2011 Low MW HA vs high MW People with  VAS pain at rest Could not
HA vs Mixed MW HA vs Knee OA  VAS pain on movement extract data
placebo
 Adverse events
Shimizu 2010 Artzdispo vs People with  Pain score Unclear how
corticosteroids Knee OA  VAS (pain on outcomes
movement?) measured.
Osteoarthritis

Skwara 2009 Durolane vs triamcinolone People with  VAS pain
Knee OA  QoL
Skwara 2009A Ostenil vs triamcinolone People with  VAS pain
Knee OA  QoL
OA Hip
Atchia 2011 Durolane vs Saline vs People with  Adverse events Data
Methylprednisolone Hip OA reported in
graphs (not
meta-
analysed);
Only
adverse
event data
extracted
Qvitsgaard 2006 Hyalgan vs Saline vs People with  Pain on walking, VAS
Methylprednisolone Hip OA  OARSI responders
Tikiz 2005 Ostenil vs Hylan G-F 20 People with  Pain VAS
Hip OA  Adverse events
Spitzer 2010 Hylan G-F 20 vs People with  WOMAC pain
Methylprednisolone Hip OA  WOMAC function
 WOMAC stiffness
 Patient’s global
Update 2014
assessment
 Adverse events
Richette 2009 Adant vs Saline People with  WOMAC pain Unlicensed
Hip OA  VAS pain formulation
 WOMAC function
 WOMAC stiffness
assessment
 Adverse events
OA Ankle
Cohen 2008 Hyalgan vs Saline People with  Adverse events Data
ankle OA reported in
graphs(not
extracted),
only adverse
event data
extracted.
Salk 2006 Hyalgan vs Saline People with  EQ5D
ankle OA  Adverse events
Witteveen 2010 Orthovisc 1 ml vs 2 ml vs People with  Adverse events Data in
3ml vs 3x1ml ankle OA median,
range- not
meta-
analysable;
only adverse
event data
Osteoarthritis

extracted
Degroot 2012 Supartz vs Saline People with  Pain VAS Unlicensed
ankle OA  Adverse events formulation
Karatosun 2008 Adant vs Exercise People with  Pain on activity, VAS Unlicensed
ankle OA  Pain at rest, VAS formulation
 Adverse events
OA Base of
thumb
Stahl 2005 Orthovisc vs People with  Pain on activity, VAS
Methylprednisolone OA of base of  Pain at rest, VAS
thumb
 Adverse events
Heyworth 2008 Synvisc vs Betamethasone People with  Adverse events Data in
vs Saline OA of base of graphs, not
thumb extracted;
only adverse
Update 2014
events data
available
Fuchs 2006 Ostenil vs Triamcinolone People with  Only reports
OA of base of Mann
thumb Whitney
variables;
not
extracted
Bahadir 2009 Ostenil vs Triamcinolone People with  Pain , VAS
OA of base of  Adverse events
thumb
OA Great toe
Munteanu 2011 Synvisc vs Saline People with  SF 36 Physical
OA of the  SF 36 Mental
great toe
assessment
 Local adverse events
Pons 2007 Ostenil vs Triamcinolone People with  Pain on walking 20 m,
OA of the VAS
great toe  Pain at rest/palpation
 Responder rate
Osteoarthritis
Knee OA
Table 212: Clinical evidence profile Knee OA- Hyalgan (licensed product) vs placebo
Quality Importance
Design Inconsistency Indirectness Imprecision Hyalgan Placebo Absolute
WOMAC pain (0-100 mm VAS) - up to 13 weeks post-injection (Better indicated by lower values) (Tsai 2003)
a
trials serious inconsistency indirectness imprecision (0.4 lower to LOW
0.19 higher)
WOMAC pain (0-100 mm VAS) - more than 13 weeks post-injection (Better indicated by lower values) (Huang 2011; Tsai 2003)
a c
2 randomised serious no serious no serious Serious none 188 186 - SMD 0.37 CRITICAL
trials inconsistency indirectness lower (0.58 to LOW
Update 2014
0.17 lower)
WOMAC function (0-100 mm VAS) - up to 13 weeks post-injection (Better indicated by lower values) (Tsai 2003)
1 randomised very no serious no serious no serious none 88 89 - SMD 0.07 LOW CRITICAL
a
trials serious inconsistency indirectness imprecision lower (0.37
lower to 0.22
higher)
WOMAC function (0-100 mm VAS) - more than 13 weeks post-injection (Better indicated by lower values) (Huang 2011; Tsai 2003)
a c
2 randomised serious no serious no serious Serious none 188 186 - SMD 0.35 CRITICAL
trials inconsistency indirectness lower (0.55 to LOW
0.14 lower)
WOMAC stiffness - More than 13 weeks post-injection (Better indicated by lower values) ) (Huang 2011)
a
1 randomised serious no serious no serious no serious none 100 98 - SMD 0.09 CRITICAL
trials inconsistency indirectness imprecision lower (0.37 MODERATE
lower to 0.19
higher)
OARSI responder criteria - more than 13 weeks post-injection- imputation as responders (Lundsgaard 2008)
c
1 randomised no serious no serious no serious Serious none 50/82 33/79 RR 1.46 192 more per IMPORTANT
trials risk of bias inconsistency indirectness (61%) (41.8%) (1.07 to 2) 1000 (from 29 MODERATE
more to 418
334
Osteoarthritis

Quality Importance
more)
OARSI responder criteria - more than 13 weeks post-injection- imputation as non-responders(Lundsgaard 2008)
c
1 randomised no serious no serious no serious Serious none 30/82 27/81 RR 1.1 33 more per IMPORTANT
trials risk of bias inconsistency indirectness (36.6%) (33.3%) (0.72 to 1000 (from 93 MODERATE
1.67) fewer to 223
more)
Joint space width (mm) - more than 13 weeks post-injection (after three courses of treatment) (Better indicated by lower values) (Jubb 2001a)
a c
1 randomised Serious no serious no serious Serious none 136 137 - SMD 0.26 IMPORTANT
trials inconsistency indirectness higher (0.02 to LOW
0.49 higher)
Joint space width (mm) (after three courses of treatment and stratified subgroups) - more than 13 weeks post-injection (Better indicated by lower values) (Jubb
Update 2014
2001b/c)
a b c
2 randomised Serious Serious no serious Serious none 136 137 - SMD 0.12 IMPORTANT
trials indirectness higher (0.28 VERY LOW
lower to 0.52
higher)
Patient global assessment (number of patients improved) - up to 13 weeks post-injection (number of patients improved (excellent/very good/good/better/somewhat
better) (Corrado 1995; Creamer 1994; FormigueraSala1995; Jorgensen 2010)
a b c
4 randomised Serious Serious no serious Serious none 36/51 19/48 RR 1.70 277 more per IMPORTANT
trials indirectness (70.6%) (39.6%) (0.79 to 1000 (from 83 VERY LOW
3.62) fewer to 1000
more)
Patient global assessment (number of patients improved) - more than 13 weeks post-injection (number of patients improved (better/somewhat/much; excellent/fair)
(Dougados 1993; Henderson 1994; Huang 2011; Huskisson 1999; Lin 2004; Lundsgaard 2008)
a c
6 randomised Serious no serious no serious Serious none 199/309 170/311 RR 1.17 (1 93 more per IMPORTANT
trials inconsistency indirectness (64.4%) (54.7%) to 1.37) 1000 (from 0 LOW
more to 202
more)
Patient global assessment (number of joints fairly good/good/very good) - up to 13 weeks post-injection (Bragantini 1987; Creamer 1994)
c
2 randomised very no serious no serious Serious none 22/31 10/30 RR 2.12 373 more per IMPORTANT
335
Osteoarthritis

Quality Importance
a
trials serious inconsistency indirectness (71%) (33.3%) (1.22 to
1000 (from 73 VERY LOW
3.7)
more to 900
more)
Safety: number of patients with injection site pain or painful intra-articular injection - more than 13 weeks post-injection (Altman 1998; Dougados 1993; FormigueraSala
1995)
a c
3 randomised Serious no serious no serious Serious none 59/239 43/243 RR 1.39 69 more per IMPORTANT
trials inconsistency indirectness (24.7%) (17.7%) (0.98 to 1000 (from 4 LOW
1.97) fewer to 172
more)
Update 2014
effects analysis.
Table 213: Clinical evidence profile: Knee OA- Hylan GF 20 (licensed product) vs placebo
Importan
Quality
No of Risk of Other Relative ce
Design Inconsistency Indirectness Imprecision Hylan GF 20 Placebo Absolute
Pain overall (0-100 mm VAS) - up to 13 weeks post-injection (Better indicated by lower values) (Moreland 1993)
c
1 randomised no serious no serious no serious Serious none 46 48 - SMD 0.07 lower CRITICAL
trials risk of bias inconsistency indirectness (0.48 lower to 0.33 MODERAT
higher) E
WOMAC pain - up to 13 weeks post-injection (Better indicated by lower values) (Cubucku 2004; Dickson 2001; Diracoglu 2009; Kotevoglu 2005)
a b c
4 randomised Serious very serious no serious Serious none 136 97 - SMD 1.24 lower CRITICAL
336
Osteoarthritis

Importan
Quality
WOMAC pain - more than 13 weeks post-injection_ single injection (Better indicated by lower values)(Chevalier2010)
a c
1 randomised Serious no serious no serious Serious none 124 129 - SMD 0.24 lower Critical
trials inconsistency indirectness (0.48 lower to 0.01 LOW
higher)
WOMAC pain - more than 13 weeks post-injection_multiple injections (Better indicated by lower values)(Kotevoglu 2005)
a
WOMAC function - up to 13 weeks post-injection (Better indicated by lower values) (Cubucku 2004; Dickson 2001; Diracoglu 2009; Kotevoglu 2005)
a b c
4 randomised Serious very serious no serious Serious none 136 97 - SMD 1.2 lower CRITICAL
Update 2014
WOMAC function- more than 13 weeks post-injection_ single injection (Better indicated by lower values)(Chevalier2010)
a c
CRITICAL
1 randomised Serious no serious no serious Serious none 124 129 - SMD 0.14 lower (0.39
WOMAC function - more than 13 weeks post-injection (Better indicated by lower values) (Kotevoglu 2005)
a
WOMAC stiffness (2 to 10 Likert) - up to 13 weeks post-injection (Better indicated by lower values) (Cubucku 2004;Diracoglu 2009; Kotevoglu 2005)
a b c
3 randomised Serious Serious no serious Serious none 83 40 - SMD 0.64 lower CRITICAL
trials indirectness (1.35 lower to 0.08 VERY LOW
higher)
WOMAC stiffness (2 to 10 Likert) - more than 13 weeks post-injection (Better indicated by lower values) (Kotevoglu 2005)
c
1 randomised very no serious no serious Serious none 21 18 - SMD 0.72 lower CRITICAL
a
trials serious inconsistency indirectness (1.37 to 0.07 lower) VERY LOW
Patient global assessment (0-100 mm VAS; where 100 is worst severity) - up to 13 weeks post-injection (Better indicated by lower values) (Kotevoglu 2005)
337
Osteoarthritis

Importan
Quality
1 randomised very no serious no serious no serious none 21 9 - SMD 1.53 lower IMPORTA
a
trials serious inconsistency indirectness imprecision (2.42 to 0.65 lower) LOW NT
Patient global assessment (0-100 mm VAS; where 100 is worst severity) - more than 13 weeks post injection (Better indicated by lower values) (Kotevoglu 2005)
c
1 randomised very no serious no serious very serious none 21 9 - SMD 0 higher (0.78 IMPORTA
a
trials serious inconsistency indirectness lower to 0.78 VERY LOW NT
higher)
Safety: number of patients with local reaction- up to 13 weeks post-injection (Cubucku 2004;Diracoglu 2009; Moreland 1993; Wobig 1998; Wobic 1999c)
a b c
5 randomised Serious Serious no serious very serious none 23/210 8/207 RR 1.81 31 more per 1000 IMPORTA
trials indirectness (11%) (3.9%) (0.36 to (from 25 fewer to VERY LOW NT
9.07) 312 more)
Update 2014
Safety: number of patients with local reaction- more than 13 weeks post injection (Kotevoglu 2005)
a c
1 randomised Serious no serious no serious very serious none 1/26 (3.8%) 0/26 RR3.00 - VERY LOW IMPORTA
trials inconsistency indirectness (0.13 to NT
70.42)
effects analysis.
Table 214: Clinical evidence profile: Knee OA- Orthovisc (licensed product) vs placebo
Importan
Quality
Design Inconsistency Indirectness Imprecision Orthovisc Placebo Absolute
338
Osteoarthritis

Importan
Quality
WOMAC pain (5 to 25 Likert) - up to 13 weeks post-injection (Better indicated by lower values) (Hizmetli 1999; Kotevoglu 2005; Kulpanza 2010; Neustadt 2005a;
Neustadt 2005b; Szegin 2005)
a b c
6 randomised serious very serious no serious Serious None 279 170 - SMD 0.99 lower (1.75 CRITICAL
trials indirectness to 0.24 lower) VERY
LOW
WOMAC pain (5 to 25 Likert) - more than 13 weeks post-injection (Better indicated by lower values) (Hizmetli 1999; Kotevoglu 2005; Kulpanza 2010; Neustadt 2005a;
Neustadt 2005b)
a b c
5 randomised serious very serious no serious Serious none 257 151 - SMD 0.57 lower (1.11 CRITICAL
LOW
WOMAC physical function (17 to 85 Likert) - up to 13 weeks post-injection (Better indicated by lower values) (Hizmetli 1999; Kotevoglu 2005; Kulpanza 2010; Szegin
Update 2014
2005)
a b c
4 randomised Serious very serious no serious Serious None 85 70 - SMD 1.21 lower (2.13 CRITICAL
LOW
WOMAC physical function (17 to 85 Likert) - more than 13 weeks post-injection (Better indicated by lower values)( Hizmetli 1999; Kotevoglu 2005; Kulpanza 2010)
a c
3 randomised Serious no serious no serious Serious None 63 51 - SMD 0.55 lower (1.04 CRITICAL
trials inconsistency indirectness to 0.06 lower) LOW
WOMAC stiffness (2 to 10 Likert) - up to 13 weeks post-injection (Better indicated by lower values) (Hizmetli 1999; Kotevoglu 2005; Kulpanza 2010)
c
3 randomised very no serious no serious Serious None 65 50 - SMD 0.27 lower (0.72 CRITICAL
a
trials serious inconsistency indirectness lower to 0.18 higher) VERY
LOW
WOMAC stiffness (2 to 10 Likert) - more than 13 weeks post-injection (Better indicated by lower values)( Kotevoglu 2005; Kulpanza 2010)
b c
2 randomised very very serious no serious Serious None 43 31 - SMD 0.59 lower (1.52 CRITICAL
a
trials serious indirectness lower to 0.35 higher) VERY
LOW
Patient global assessment (0 to 100 mm VAS; where 100 is worst severity) - up to 13 weeks post-injection (Better indicated by lower values) (Kotevoglu 2005)
1 randomised very no serious no serious no serious None 20 9 - SMD 1.53 lower (2.42 IMPORTA
a
trials serious inconsistency indirectness imprecision to 0.63 lower) LOW NT
Patient global assessment (0 to 100 mm VAS; where 100 is worst severity) - more than 13 weeks post-injection (Better indicated by lower values) (Kotevoglu 2005)
339
Osteoarthritis

Importan
Quality
c
1 randomised very no serious no serious very serious None 20 9 - SMD 0 higher (0.79 IMPORTA
a
trials serious inconsistency indirectness lower to 0.79 higher) VERY NT
LOW
Safety: number of patients with local skin rash - more than 13 weeks post-injection (Brandt 2001; Neustadt 2005a; Neustadt 2005b)
a c
3 randomised Serious no serious no serious very serious None 9/361 14/358 RR 0.63 14 fewer per 1000 IMPORTA
trials inconsistency indirectness (2.5%) (3.9%) (0.28 to (from 28 fewer to 18 VERY NT
1.45) more) LOW
Update 2014
effects analysis.
Table 215: Clinical evidence profile: Knee OA- BioHy (licensed product) vs placebo
BioHy Quality Importance

Design Inconsistency Indirectness Imprecision (Arthrease, Placebo Absolute
Euflexxa)
WOMAC pain (more than 13 weeks post-injection) (Better indicated by lower values)(Altman 2009)
a
0.27 higher)
WOMAC Stiffness (more than 13 weeks post-injection) (Better indicated by lower values) (Altman 2009)
a
340
Osteoarthritis
BioHy Quality Importance

Design Inconsistency Indirectness Imprecision (Arthrease, Placebo Absolute
Euflexxa)
0.3 higher)
WOMAC function (more than 13 weeks post injection) (Better indicated by lower values) (Altman 2009)
a
higher)
OARSI responders - up to 13 weeks post-injection (Altman 2009)
a
1 randomised serious no serious no serious no serious none 173/291 167/295 RR 1.05 28 more per IMPORTANT
trials inconsistency indirectness imprecision (59.5%) (56.6%) (0.91 to 1000 (from 51 MODERATE
1.21) fewer to 119
more)
OARSI responders - more than 13 weeks post injection (Altman 2009)
Update 2014
a b
1 randomised serious no serious no serious serious none 169/254 155/264 RR 1.13 76 more per IMPORTANT
trials inconsistency indirectness (66.5%) (58.7%) (0.99 to 1000 (from 6 LOW
1.3) fewer to 176
more)
Patient global assessment (more than 13 weeks post-injection) (Better indicated by lower values)
a
1 randomised serious no serious no serious no serious none 293 295 - SMD 0.14 lower IMPORTANT
0.02 higher)
HRQoL SF36 (more than 13 weeks post injection) (Better indicated by lower values) (Altman 2009)
a
1 randomised serious no serious no serious no serious none 293 295 - SMD 0.22 higher IMPORTANT
higher)
Safety: number of adverse events for injection site pain - more than 13 weeks post-injection (Altman 2009)
a b
1 randomised serious no serious no serious serious none 18/25 11/24 RR 1.57 261 more per IMPORTANT
trials inconsistency indirectness (72%) (45.8%) (0.95 to 1000 (from 23 LOW
2.59) fewer to 729
more)
341
Osteoarthritis
Table 216: Clinical evidence profile: Knee OA- Durolane (licensed product) vs placebo
Quality Importance
Design Inconsistency Indirectness Imprecision Durolane Placebo Absolute
WOMAC pain (change from baseline; 0 to 20 Likert) - up to 12 weeks post injection (Better indicated by lower values) (Altman 1998; Altman 2004)
a
2 randomised serious no serious no serious no serious None 344 348 - SMD 0.18 higher CRITICAL
higher)
WOMAC pain (change from baseline; 0 to 20 Likert) - more than 13 weeks post injection (Better indicated by lower values) (Altman 1998)
Update 2014
a
0.31 higher)
WOMAC physical function (change from baseline; 0 to 68 Likert) - up to 13 weeks (Better indicated by lower values) (Altman 2004)
1 randomised no serious no serious no serious no serious None 172 174 - SMD 0.14 higher CRITICAL
0.35 higher)
WOMAC physical function (change from baseline; 0 to 68 Likert) - more than 13 weeks (Better indicated by lower values) (Altman 2004)
1 randomised no serious no serious no serious no serious none 172 174 - SMD 0.12 higher CRITICAL
0.34 higher)
WOMAC stiffness (change from baseline; 0 to 8 Likert) - up to 13 weeks post injection (Better indicated by lower values) ) (Altman 1998; Altman 2004)
a
0.28 higher)
WOMAC stiffness (change from baseline; 0 to 8 Likert) - more than 13 weeks post injection (Better indicated by lower values) (Altman 2004)
higher)
342
Osteoarthritis

Quality Importance
Design Inconsistency Indirectness Imprecision Durolane Placebo Absolute
Safety: number of patients with adverse events related to injection only (Altman 2004)
b
1 randomised no serious no serious no serious very serious none 1/173 2/174 RR 0.5 6 fewer per 1000 IMPORTANT
trials risk of bias inconsistency indirectness (0.6%) (1.1%) (0.05 to (from 11 fewer to LOW
5.49) 52 more)
Update 2014
Table 217: Clinical evidence profile: Knee OA- Suplasyn (licensed product) vs placebo
Relative Quality Importance

No of Other
Design Risk of bias Inconsistency Indirectness Imprecision Suplasyn Placebo (95% Absolute
studies considerations
CI)
WOMAC pain (0-10 cm VAS) – up to 13 weeks (Better indicated by lower values) (Petrella 2002)
a
1 randomised no serious no serious no serious serious none 25 28 - SMD 0.29 lower CRITICAL
trials risk of bias inconsistency indirectness (0.83 lower to 0.25 MODERATE
higher)
WOMAC function (0-10 cm VAS) – up to 13 weeks (Better indicated by lower values) (Petrella 2002)
a
trials risk of bias inconsistency indirectness (1.02 lower to 0.07 MODERATE
higher)
343
Osteoarthritis
Table 218: Clinical evidence profile: Knee OA- Hyalgan (licensed product) vs NSAID
Importan
Quality
Design Inconsistency Indirectness Imprecision Hyalgan NSAID Absolute
Pain (0-100 mm VAS) - up to 13 weeks post-injection (Better indicated by lower values) (Altman 1998)
a
trials inconsistency indirectness imprecision (0.17 lower to 0.33 MODERAT
higher) E
Pain (0-100 mm VAS) - more than 13 weeks post-injection (Better indicated by lower values) (Altman 1998)
a
1 randomised serious no serious no serious no serious none 105 111 - SMD 0.13 lower (0.4 CRITICAL
trials inconsistency indirectness imprecision lower to 0.14 higher) MODERAT
E
Safety: number of patients with injection site pain - more than 13 weeks post-injection (Altman 1998)
a
Update 2014
1 randomised serious no serious no serious no serious none 38/164 14/16 RR 2.7 146 more per 1000 IMPORTA
trials inconsistency indirectness imprecision (23.2%) 3 (1.52 to (from 45 more to 326 MODERAT NT
(8.6%) 4.79) more) E
Table 219: Clinical evidence profile: Knee OA- Hylan GF-20(licensed product) vs NSAID
Importan
Quality
No of Risk of Imprecisio Other Relative ce
Design Inconsistency Indirectness Hylan G-F 20 NSAID Absolute
studies bias n considerations (95% CI)
Pain overall (0-100 mm VAS) - up to 13 weeks post-injection (Better indicated by lower values) (Adams 1995)
b
1 randomised very no serious no serious Serious none 25 32 - SMD 0.18 lower (0.71 CRITICAL
a
LOW
Pain overall (0-100 mm VAS) - more than 13 weeks post-injection (Better indicated by lower values) (Adams 1995)
b
a
LOW
344
Osteoarthritis
WOMAC pain (0-100 mm VAS) - up to 13 weeks post-injection (Better indicated by lower values) (Dickson 2001)
a b
1 randomised Serious no serious no serious Serious none 53 55 - SMD 0.41 lower (0.79 LOW CRITICAL
trials inconsistency indirectness to 0.02 lower)
WOMAC function (0-100 mm VAS) - up to 13 weeks post-injection (Better indicated by lower values) (Dickson 2001)
a b
1 randomised Serious no serious no serious Serious none 53 55 - SMD 0.21 lower (0.59 CRITICAL
Patient overall assessment of treatment (number of patients excellent, very good, good) - up to 13 weeks post-injection (number of patients very good or good)
(Dickson 2001)
a b
1 randomised Serious no serious no serious Serious none 29/42 35/42 RR 0.83 142 fewer per 1000 IMPORTA
trials inconsistency indirectness (69%) (83.3% (0.65 to (from 292 fewer to 50 LOW NT
) 1.06) more)
Patient overall assessment of treatment (number of patients excellent, very good, good) - more than 13 weeks post-injection (number of patients excellent/very
good/good) (Adams 1995)
b
1 randomised very no serious no serious Serious none 17/27 12/31 RR 1.63 244 more per 1000 IMPORTA
a
trials serious inconsistency indirectness (63%) (38.7% (0.96 to (from 15 fewer to 681 VERY NT
Update 2014
) 2.76) more) LOW
Safety: number of patients with local reactions - up to 13 weeks post-injection (Dickson 2001)
a
1 randomised Serious no serious no serious very none 7/50 4/52 RR 1.82 63 more per 1000 IMPORTA
b
trials inconsistency indirectness serious (14%) (7.7%) (0.57 to (from 33 fewer to 372 VERY NT
5.84) more) LOW
Table 220: Clinical evidence profile: Knee OA- Suplasyn (licensed product) vs NSAID
Relativ Importan
Quality
No of Risk of Imprecisio Other e ce
Design Inconsistency Indirectness Suplasyn NSAID Absolute
studies bias n considerations (95%
CI)
WOMAC pain (0-10 cm VAS) (Better indicated by lower values) (Petrella 2002)
a
345
Osteoarthritis

higher) E
WOMAC function (0-10 cm VAS) (Better indicated by lower values) (Petrella 2002)
a
higher) E
Table 221: Clinical evidence profile: Knee OA- Hylan GF 20 (licensed product) vs Triamcinolone
Relativ Qualit Importan

No of Risk of Imprecisio Other e y ce
Design Inconsistency Indirectness Hylan G-F 20 triamcinolone Absolute
Update 2014
CI)
WOMAC pain walking on a flat surface (Question 1: 0-4 Likert) - up to 13 weeks post-injection (Better indicated by lower values) (Caborn 2004)
a b
trials inconsistency indirectness (0.7 to 0.16 lower) LOW
WOMAC pain walking on a flat surface (Question 1: 0-4 Likert) – more than 13 weeks post-injection (Better indicated by lower values) (Caborn 2004)
a b
lower)
WOMAC function (0-68 Likert) - 5 to 13 weeks post-injection (Better indicated by lower values) (Caborn 2004)
a b
lower)
WOMAC function (0-68 Likert) - 14 to 26 weeks post-injection (Better indicated by lower values) (Caborn 2004)
a b
lower)
Patient global overall assessment (0-100 mm VAS) - 5 to 13 weeks post-injection (Better indicated by lower values) (Caborn 2004)
a b
1 randomised serious no serious no serious serious none 113 102 - SMD 0.54 lower LOW IMPORTA
trials inconsistency indirectness (0.81 to 0.27 NT
346
Osteoarthritis
lower)
Patient global overall assessment (0-100 mm VAS) - 14 to 26 weeks post-injection (Better indicated by lower values) (Caborn 2004)
a b
1 randomised serious no serious no serious serious none 113 102 - SMD 0.57 lower LOW IMPORTA
trials inconsistency indirectness (0.84 to 0.3 lower) NT
Table 222: Clinical evidence profile: Knee OA- Durolane (licensed product) vs Triamcinolone
Importan
Update 2014
Relativ Quality
No of Risk of Imprecisio Other triamcinol e ce
Design Inconsistency Indirectness Durolane Absolute
studies bias n considerations one (95%
CI)
VAS pain - up to 13 weeks post-injection (Better indicated by lower values) (Skwara 2009)
b
1 randomised very no serious no serious serious none 30 30 - SMD 0.07 lower (0.58 CRITICAL
a
LOW
Table 223: Clinical evidence profile: Knee OA- Ostenil (licensed product) vs triamcinolone
Relativ Importan
Quality
No of Risk of Imprecisio Other Triamcinolo e ce
Design Inconsistency Indirectness Ostenil Absolute
studies bias n considerations ne (95%
CI)
347
Osteoarthritis
VAS pain - up to 13 weeks post-injection (Better indicated by lower values) (Skwara 2009A)
a
1 randomised very no serious no serious serious none 21 21 - SMD 0.07 higher (0.54 CRITICAL
LOW
Table 224: Clinical evidence profile: Knee OA- Hyalgan (licensed product) vs methylprednisolone
Importan
Quality
No of Risk of Imprecisio Other methylprednisolone Relative ce
Design Inconsistency Indirectness Hyalgan Absolute
studies bias n considerations acetate (95% CI)
Patient global (number of patients very good or good, excellent or /good) - up to 13 weeks post-injection (Frizzerio 2002; Leardini 1991; Pietrogrande 1991)
a b
3 randomise serious very serious no serious very none 62/111 54/102 RR 1.14 74 more per 1000 CRITICAL
c
d trials indirectness serious (55.9%) (52.9%) (0.43 to (from 302 fewer to VERY
Update 2014
3.05) 1000 more) LOW
Patient global (number of patients very good or good, excellent or /good) - more than 13 weeks post-injection (Frizzerio 2002)
a c
1 randomise Serious no serious no serious Serious none 30/38 24/32 RR 1.05 37 more per 1000 IMPORTA
d trials inconsistency indirectness (78.9%) (75%) (0.81 to (from 142 fewer to LOW NT
1.36) 270 more)
effects analysis.
Table 225: Clinical evidence profile: Knee OA- Orthovisc (licensed product) vs methylprednisolone
Importan
Quality
No of Risk of Imprecisio Other 6- Relative ce
Design Inconsistency Indirectness Orthovisc Absolute
studies bias n considerations methylpredniso (95% CI)
348
Osteoarthritis
lone acetate
Safety: number of patients reporting skin adverse events - more than 13 weeks post-injection (Tascioglu 2003)
1 randomise very no serious no serious very none 2/28 1/27 RR 1.93 34 more per 1000 IMPORTA
a b
d trials serious inconsistency indirectness serious (7.1%) (3.7%) (0.19 to (from 30 fewer to VERY NT
20.05) 706 more) LOW
Safety: number of patients reporting knee pain after injection - more than 13 weeks post-injection (Tascioglu 2003)
1 randomise very no serious no serious very none 6/28 5/27 RR 1.16 30 more per 1000 IMPORTA
a b
d trials serious inconsistency indirectness serious (21.4%) (18.5%) (0.4 to (from 111 fewer VERY NT
3.35) to 435 more) LOW
Table 226: Clinical evidence profile: Knee OA- Orthovisc (licensed product) vs betamethasone
Update 2014
Importan
Quality
No of Risk of Imprecisio Other betametha Relative ce
Design Inconsistency Indirectness Orthovisc Absolute
studies bias n considerations sone (95% CI)
WOMAC function (0-100 mm VAS) - up to 13 weeks post-injection (Better indicated by lower values) (Tekeoglu 1998)
b
a
trials serious inconsistency indirectness (1.73 to 0.4 lower) VERY
LOW
Patient global assessment (number of patients good or very good) - up to 13 weeks post-injection (Tekeoglu 1998)
b
1 randomised very no serious no serious serious none 15/20 8/20 RR 1.88 352 more per 1000 IMPORTA
a
trials serious inconsistency indirectness (75%) (40%) (1.04 to (from 16 more to VERY NT
3.39) 956 more) LOW
349
Osteoarthritis
Table 227: Clinical evidence profile: Knee OA- Hylan GF-20 (licensed product) vs Physiotherapy
No of Relativ Importan
Quality
studies Risk of Imprecisio Other physical e ce
Design Inconsistency Indirectness Hylan G-F 20 Absolute
bias n considerations therapy (95%
CI)
WOMAC pain - up to 13 weeks post-injection (Better indicated by lower values) (Atamaz 2005)
b
a
trials serious inconsistency indirectness to 0.28 lower) VERY
LOW
WOMAC pain - more than 13 weeks post-injection (Better indicated by lower values) (Atamaz 2005)
b
a
LOW
Update 2014
WOMAC physical function - up to 13 weeks post-injection (Better indicated by lower values) (Atamaz 2005)
b
a
LOW
WOMAC physical function - more than 13 weeks post-injection (Better indicated by lower values) (Atamaz 2005)
1 randomised very no serious no serious very none 20 20 - SMD 0.06 higher CRITICAL
a b
trials serious inconsistency indirectness serious (0.56 lower to 0.68 VERY
higher) LOW
SF-36 physical functioning - up to 13 weeks post-injection (Better indicated by lower values) (Atamaz 2005)
b
1 randomised very no serious no serious serious none 20 20 - SMD 0.39 higher IMPORTA
a
trials serious inconsistency indirectness (0.23 lower to 1.02 VERY NT
higher) LOW
SF-36 physical functioning - more than 13 weeks post-injection (Better indicated by lower values) (Atamaz 2005)
b
1 randomised very no serious no serious serious none 20 20 - SMD 0.04 higher IMPORTA
a
trials serious inconsistency indirectness (0.58 lower to 0.66 VERY NT
higher) LOW
350
Osteoarthritis
Table 228: Clinical evidence profile: Knee OA- Orthovisc (licensed product) vs Physiotherapy
Relativ Importan
Quality
No of Risk of Other physical e ce
Design Inconsistency Indirectness Imprecision Orthovisc Absolute
studies bias considerations therapy (95%
CI)
WOMAC pain - up to 13 weeks post-injection (Better indicated by lower values) (Atamaz 2005)
b
a
trials serious inconsistency indirectness (0.86 lower to 0.39 VERY
higher) LOW
WOMAC pain - more than 13 weeks post-injection (Better indicated by lower values) (Atamaz 2005)
Update 2014
a
WOMAC function - up to 13 weeks post-injection (Better indicated by lower values) (Atamaz 2005)
b
a
higher) LOW
WOMAC function - more than 13 weeks post-injection (Better indicated by lower values) (Atamaz 2005)
b
a
higher) LOW
b
1 randomised very no serious no serious serious none 20 20 - SMD 0.65 lower IMPORTA
a
trials serious inconsistency indirectness (1.29 to 0.01 lower) VERY NT
LOW
b
1 randomised very no serious no serious very serious none 20 20 - SMD 1.14 lower IMPORTA
a
LOW
351
Osteoarthritis
Table 229: Clinical evidence profile: Knee OA-Hyalgan (licensed product) following knee arthroscopy with lavage vs conventional treatment (knee
arthroscopy with lavage alone)
Relativ Importan
Quality
No of Risk of Imprecisio Other Conventional e ce
studies bias n considerations therapy (95%
CI)
Update 2014
Pain overall (0-100 mm VAS) - more than 13 weeks post-injection (Better indicated by lower values) (Listrat 1997)
c
1 randomise very no serious no serious serious none 19 17 - SMD 0.53 lower CRITICAL
a
d trials serious inconsistency indirectness (1.2 lower to 0.14 VERY
higher) LOW
Quality of life (AIMS: total of 12 items) - more than 13 weeks post-injection (Better indicated by lower values) (Listrat 1997)
1 randomise very no serious no serious very none 19 17 - SMD 0.16 lower IMPORTA
a c
d trials serious inconsistency indirectness serious (0.82 lower to VERY NT
0.49 higher) LOW
Joint space width (mm) - more than 13 weeks post-injection (Better indicated by lower values) (Listrat 1997)
c
1 randomise very no serious no serious serious none 19 17 - SMD 0.63 higher IMPORTA
a
d trials serious inconsistency indirectness (0.04 lower to 1.3 VERY NT
higher) LOW
352
Osteoarthritis
Table 230: Clinical evidence profile: Knee OA-Hylan GF-20 (licensed product) vs ‘conventional treatment for osteoarthritis’ (the paper provides no more
detail on the control arm)
Importan
Quality
No of Risk of Other Conventional Relative ce
Design Inconsistency Indirectness Imprecision Hylan G-F 20 Absolute
studies bias considerations treatment (95% CI)
WOMAC pain - more than 13 weeks post-injection (Better indicated by lower values) (Kahan 2003a)
a b
1 randomise serious no serious no serious serious none 251 246 - SMD 0.6 lower CRITICAL
d trials inconsistency indirectness (0.78 to 0.42 LOW
lower)
WOMAC function - more than 13 weeks post-injection (Better indicated by lower values) (Kahan 2003a)
a b
1 randomise serious no serious no serious serious none 251 247 - SMD 0.61 lower LOW CRITICAL
d trials inconsistency indirectness (0.79 to 0.43
lower)
Patient global evaluation of effectiveness (good or satisfactory) - more than 13 weeks post-injection (Kahan 2003a)
Update 2014
a
1 randomise serious no serious no serious no serious none 186/253 129/253 RR 1.44 224 more per 1000 IMPORTA
d trials inconsistency indirectness imprecision (73.5%) (51%) (1.25 to (from 127 more to MODERAT NT
1.66) 337 more) E
Table 231: Clinical evidence profile: Knee OA- Artz (unlicensed product) vs placebo
Importan
Quality
No of Other placeb Relative ce
Design Risk of bias Inconsistency Indirectness Imprecision Artz Absolute
studies considerations o (95% CI)
Pain (100 mm VAS) - up to 13 weeks post-injection (Better indicated by lower values) (Karlsson 2002a; Lohmander 1996; Puhl 1993)
3 randomised no serious no serious no serious no serious none 281 226 - SMD 0.17 lower CRITICAL
higher)
Pain (100 mm VAS) - more than 13 weeks post-injection (Better indicated by lower values) (Karlsson 2002a; Lohmander 1996)
353
Osteoarthritis
a
2 randomised serious no serious no serious no serious none 186 126 - SMD 0 higher (0.24 CRITICAL
trials inconsistency indirectness imprecision lower to 0.23 MODERAT
higher) E
WOMAC pain (0-20 Likert) - up to 13 weeks post-injection (Better indicated by lower values) (Day 2004)
b
a
trials serious inconsistency indirectness lower to 0.02 VERY LOW
higher)
WOMAC function (0-68 Likert) - up to 13 weeks post-injection (Better indicated by lower values) (Day 2004)
b
a
trials serious inconsistency indirectness (0.49 lower to 0.04 VERY LOW
higher)
WOMAC stiffness (0-8 Likert) - up to 13 weeks post-injection (Better indicated by lower values) (Day 2004)
b
1 randomised very no serious no serious Serious none 108 115 -
SMD 0.24 lower CRITICAL
a
trials serious inconsistency indirectness (0.51 lower to 0.02 VERY LOW
higher)
Update 2014
Patient global assessment (number of patients improved) - up to 13 weeks post-injection (Lohmander 1996; Puhl 1993; Schichikawa 1983a; Schichikawa 1983b))
a b
4 randomised serious no serious no serious Serious none 264/342 234/3 RR 1.15 101 more per 1000 IMPORTA
trials inconsistency indirectness (77.2%) 48 (1.05 to (from 34 more to LOW NT
(67.2% 1.26) 175 more)
)
Patient global assessment (number of patients improved) - more than 13 weeks post-injection (Lohmander 1996)
a b
1 randomised serious no serious no serious Serious none 58/96 43/93 RR 1.31 (1 143 more per 1000 IMPORTA
trials inconsistency indirectness (60.4%) (46.2% to 1.72) (from 0 more to 333 LOW NT
) more)
Table 232: Clinical evidence profile: Knee OA- Adant (unlicensed product) vs placebo
Importan
Quality
No of Risk of Imprecisio Other Placeb Relative ce
Design Inconsistency Indirectness Adant Absolute
studies bias n considerations o (95% CI)
354
Osteoarthritis
OARSI responder criteria (more than 13 weeks post injection) (Navarro 2011)
a
1 randomise no no serious no serious serious none 120/149 100/1 RR 1.22 145 more per IMPORTA
d trials serious inconsistency indirectness (80.5%) 52 (1.07 to 1000 (from 46 MODERAT NT
risk of (65.8% 1.41) more to 270 E
bias ) more)
Patient Global assessment (more than 13 weeks post injection) (Navarro 2011)
a
1 randomise no no serious no serious serious none 111/149 88/15 RR 1.29 168 more per IMPORTA
d trials serious inconsistency indirectness (74.5%) 2 (1.09 to 1000 (from 52 MODERAT NT
risk of (57.9% 1.52) more to 301 E
bias ) more)
Table 233: Clinical evidence profile: Knee OA- NRD-101 (unlicensed product) vs placebo
Update 2014
Qualit Importan
NRD-101 (Suvenyl) y ce
No of Risk of Other Contr Relative
Design Inconsistency Indirectness Imprecision versus placebo (saline Absolute
studies bias considerations ol (95% CI)
plus oral placebo)
Pain (0-100 mm VAS) (more than 13 weeks post injection) (Better indicated by lower values) (Pham 2004)
1 randomise no no serious no serious no serious none 131 43 - SMD 0.04 higher CRITICAL
d trials serious inconsistency indirectness imprecision (0.31 lower to HIGH
risk of 0.38 higher)
bias
Joint space width (percentage of progressors: joint space narrowing greater than 0.5 mm) (Pham 2004)
a
1 randomise no no serious no serious very serious none 23/131 17/85 RR 0.88 24 fewer per 1000 IMPORTA
d trials serious inconsistency indirectness (17.6%) (20%) (0.5 to (from 100 fewer LOW NT
risk of 1.54) to 108 more)
bias
Patient global assessment (0-100 mm VAS) change between baseline and 45 to 52 weeks post-injection (Better indicated by lower values) (Pham 2004)
1 randomise no no serious no serious no serious none 131 43 - SMD 0.05 higher IMPORTA
d trials serious inconsistency indirectness imprecision (0.29 lower to HIGH NT
bias
Patient assessment of treatment efficacy (no. of patients rating very good or good versus mod, bad or very bad (Pham 2004)
355
Osteoarthritis

Qualit Importan
NRD-101 (Suvenyl) y ce
No of Risk of Other Contr Relative
Design Inconsistency Indirectness Imprecision versus placebo (saline Absolute
studies bias considerations ol (95% CI)
plus oral placebo)
1 randomise no no serious no serious no serious none 86/120 57/75 RR 0.94 46 fewer per 1000 IMPORTA
d trials serious inconsistency indirectness imprecision (71.7%) (76%) (0.8 to (from 152 fewer HIGH NT
risk of 1.12) to 91 more)
bias
Safety: number of patients reporting knee pain during or after IA injection (Pham 2004)
a
1 randomise no no serious no serious very serious none 31/131 16/85 RR 1.26 49 more per 1000 IMPORTA
d trials serious inconsistency indirectness (23.7%) (18.8% (0.73 to (from 51 fewer to LOW NT
risk of ) 2.15) 216 more)
bias
Update 2014
Table 234: Clinical evidence profile: Knee OA- Artz (unlicensed product) vs corticosteroid
Relativ Importan
Quality
No of Risk of Imprecisio Other e ce
Design Inconsistency Indirectness Artz corticosteroid Absolute
CI)
VAS pain - up to 13 weeks post-injection (Better indicated by lower values) (Shimizu 2010)
b
a
LOW
VAS pain - more than 13 weeks post injection (Better indicated by lower values) (Shimizu 2010)
b
a
LOW
356
Osteoarthritis
Table 235: Clinical evidence profile: Knee OA- Artz (unlicensed product) vs exercise
Importan
Quality
Design Inconsistency Indirectness Imprecision Artz Exercise Absolute
VAS pain (more than 13 weeks) (Better indicated by lower values) (Kawasaki 2009)
1 randomised very no serious no serious no serious none 42 45 - SMD 0.03 higher (0.39 CRITICAL
a
trials serious inconsistency indirectness imprecision lower to 0.45 higher) LOW
OMERACT OARSI responder (more than 13 weeks) (Kawasaki 2009)
b
1 randomised very no serious no serious very serious none 22/42 25/45 RR 0.94 33 fewer per 1000 VERY IMPORTA
a
trials serious inconsistency indirectness (52.4%) (55.6%) (0.64 to (from 200 fewer to LOW NT
1.39) 217 more)
Update 2014
Table 236: Clinical evidence profile: Knee OA- Hyalgan (licensed product) vs Hylan GF-20 (licensed product)
Importan
Quality
No of Risk of Imprecisio Other Hylan G-F Relative ce
studies bias n considerations 20 (95% CI)
Safety: number of patients with local reaction (acute inflammation and pain) (Brown 2003)
1 randomised very no serious no serious very none 0/25 6/29 RR 0.09 188 fewer per 1000 IMPORTA
a b
trials serious inconsistency indirectness serious (0%) (20.7%) (0.01 to 1.5) (from 205 fewer to 103 VERY NT
more) LOW
357
Osteoarthritis
Table 237: Clinical evidence profile: Knee OA-BioHy (licensed product) vs Hylan GF-20 (licensed product)
Importan
BioHy Quality
No of Risk of Other Hylan G-F 20 Relative ce
Design Inconsistency Indirectness Imprecision (Arthrease, Absolute
studies bias considerations (Synvisc) (95% CI)
Euflexxa)
WOMAC pain (0-100 mm VAS) - up to 13 weeks post-injection (Better indicated by lower values) (Kirchner 2005)
1 randomise no no serious no serious no serious none 160 161 - SMD 0.19 lower CRITICAL
bias
WOMAC physical function (0-100 mm VAS) - up to 13 weeks post-injection (Better indicated by lower values) (Kirchner 2005)
a
Update 2014
1 randomise no no serious no serious serious none 157 158 - SMD 0.27 lower CRITICAL
d trials serious inconsistency indirectness (0.49 to 0.05 MODERAT
risk of lower) E
bias
WOMAC stiffness (0-100 mm VAS) - up to 13 weeks post-injection (Better indicated by lower values) (Kirchner 2005)
1 randomise no no serious no serious no serious none 157 158 - SMD 0.19 lower CRITICAL
bias
Patient assessment of treatment (number of patients very satisfied or satisfied) - up to 13 weeks post-injection (Kirchner 2005)
1 randomise no no serious no serious no serious none 127/157 119/158 RR 1.07 53 more per IMPORTA
d trials serious inconsistency indirectness imprecision (80.9%) (75.3%) (0.96 to 1000 (from 30 HIGH NT
risk of 1.21) fewer to 158
bias more)
358
Osteoarthritis
Table 238: Clinical evidence profile: Knee OA- Orthovisc (licensed product) vs Hylan GF-20 (licensed product)
Importan
Quality
No of Risk of Other Hylan G-F Relative ce
studies bias considerations 20 (95% CI)
WOMAC pain (0-20 or 5-25 Likert) - up to 13 weeks post-injection (Better indicated by lower values) (Atamaz 2005; Karatay 2004; Kotevoglu 2005)
b c
3 randomised very serious no serious serious none 60 61 - SMD 0.2 higher (0.34 CRITICAL
a
trials serious indirectness lower to 0.74 higher) VERY
LOW
WOMAC pain (0-20 or 5-25 Likert) - more than 13 weeks post-injection (Better indicated by lower values) (Atamaz 2005; Kotevoglu 2005)
c
2 randomised very no serious no serious serious none 40 41 - SMD 0.15 higher CRITICAL
a
higher) LOW
WOMAC function (0-68 or 17-85 Likert) - up to 13 weeks post-injection (Better indicated by lower values) (Atamaz 2005; Karatay 2004; Kotevoglu 2005)
3 randomised very no serious no serious no serious none 60 61 - SMD 0.03 higher CRITICAL
a
Update 2014
trials serious inconsistency indirectness imprecision (0.33 lower to 0.39 LOW
higher)
WOMAC function (0-68 or 17-85 Likert) - more than 13 weekspost-injection (Better indicated by lower values) (Atamaz 2005; Kotevoglu 2005)
c
2 randomised very no serious no serious Serious none 40 41 - SMD 0.12 higher CRITICAL
a
higher) LOW
WOMAC stiffness (0-8 or 2-10 Likert) - up to 13 weeks post-injection (Better indicated by lower values) (Karatay 2004; Kotevoglu 2005)
b
2 randomised very Serious no serious no serious none 40 41 - SMD 0.01 higher CRITICAL
a c
trials serious indirectness imprecision (0.43 lower to 0.45 VERY
higher) LOW
WOMAC stiffness (0-8 or 2-10 Likert) - more than 13 weeks post-injection (Better indicated by lower values) (Kotevoglu 2005)
c
a
higher) LOW
Patient global assessment (0-100 mm VAS where 100 is worst severity) - up to 13 weeks post-injection (Better indicated by lower values) (Kotevoglu 2005)
c
a
LOW
Patient global assessment (0-100 mm VAS where 100 is worst severity) - more than 13 weeks post-injection (Better indicated by lower values) (Kotevoglu 2005)
359
Osteoarthritis

Importan
Quality
No of Risk of Other Hylan G-F Relative ce
studies bias considerations 20 (95% CI)
c
a
LOW
1 randomised very no serious no serious no serious none 20 20 - SMD 1.32 lower IMPORTA
a
trials serious inconsistency indirectness imprecision (2.01 to 0.63 lower) LOW NT
c
1 randomised very no serious no serious Serious none 20 20 - SMD 1.08 lower IMPORTA
a
LOW
Safety: number of patients with local adverse event (Atamaz 2005; Kotevoglu 2005)
Update 2014
c
2 randomised very no serious no serious very serious none 4/46 2/46 RR 2 (0.39 43 more per 1000 IMPORTA
a
trials serious inconsistency indirectness (8.7%) (4.3%) to 10.34) (from 27 fewer to VERY NT
406 more) LOW
effects analysis.
Table 239: Clinical evidence profile: Knee OA- Hylan GF20 (licensed product) vs Sinovial (licensed product)
Quality assessment No patients Effect
No of Risk of Other Relative Quality Importance
Design Inconsistency Indirectness Imprecision Hylan Sinovial Absolute
WOMAC pain - less than 13 weeks follow up (Better indicated by lower values) (Pavelka 2011
a
1 randomised serious no serious no serious no serious none 188 192 - SMD 0.07 CRITICAL
trials inconsistency indirectness imprecisio higher MODERATE
360
Osteoarthritis
n (0.13 lower
to 0.27
higher)
WOMAC pain - more than 13 weeks follow up (Better indicated by lower values) Pavelka 2011
a
1 randomised serious no serious no serious no serious none 188 192 - SMD 0 MODERATE CRITICAL
trials inconsistency indirectness imprecisio higher (0.2
n lower to
0.2 higher)
Adverse events related to injection- more than 13 weeks follow up Pavelka 2011
a
1 randomised serious no serious no serious very none 4/189 1/192 RR 4.06 (0.46 20 fewer CRITICAL
b
trials inconsistency indirectness serious (2.1%) (0.5%) to 36.02) per 1000 VERY LOW
(from 10
fewer to 40
more)
Update 2014
Table 240: Clinical evidence profile: Knee OA- Adant (unlicensed product) vs Hyalgan (licensed product)
Importan
Quality
No of Risk of Imprecisio Other Hyalga Relative ce
Design Inconsistency Indirectness Adant Absolute
studies bias n considerations n (95% CI)
Patient global assessment (number of patients excellent/good) - up to 13 weeks post-injection (Roman 2000)
b
a
trials serious inconsistency indirectness (50%) (21.1% (0.93 to (from 15 fewer to 1000 VERY NT
) 6.09) more) LOW
Patient global assessment (number of patients excellent/good) - more than 13 weeks post-injection (Roman 2000)
b
a
trials serious inconsistency indirectness (33.3%) (15.8% (0.67 to 6.7) (from 52 fewer to 900 VERY NT
) more) LOW
Safety: number of painful injections - less than 13 weeks post-injection (Roman 2000)
1 randomised very no serious no serious very none 6/30 2/19 RR 1.9 (0.43 95 more per 1000 IMPORTA
361
Osteoarthritis
a b
trials serious inconsistency indirectness serious (20%) (10.5% to 8.46) (from 60 fewer to 785 VERY NT
) more) LOW
Table 241: Clinical evidence profile: Knee OA- Fermathron (licensed product) vs Hyalart (unlicensed product)
Qualit Importan
No of Risk of Other Relative y ce
Design Inconsistency Indirectness Imprecision Fermathron Hyalart Absolute
Pain (0-100 mm VAS) - up to13 weeks post-injection (Better indicated by lower values) (McDonald 2000)
Update 2014
higher)
Patient global assessment (number of patients much better/better) - up to 13 weeks post-injection (McDonald 2000)
1 randomised no serious no serious no serious no serious none 87/125 92/127 RR 0.96 29 fewer per 1000 IMPORTA
trials risk of bias inconsistency indirectness imprecision (69.6%) (72.4%) (0.82 to (from 130 fewer to HIGH NT
1.13) 94 more)
Table 242: Clinical evidence profile: Knee OA- Hylan GF 20 (licensed product) vs Variofill (unlicensed product)
Qualit Importan
Design Inconsistency Indirectness Imprecision Hylan GF 20 Variofill Absolute
VAS Pain (0-100 mm VAS) - up to 13 weeks post-injection (Better indicated by lower values) (Iannitti 2012)
1 randomised Serious no serious no serious Very serious none 20 20 - SMD 0.10 lower CRITICAL
b
trials risk of inconsistency indirectness imprecision (0.72 lower to 0.52 VERY
a
bias higher) LOW
VAS pain- more than 13 weeks follow up (Iannitti 2012)
362
Osteoarthritis

Qualit Importan
Design Inconsistency Indirectness Imprecision Hylan GF 20 Variofill Absolute
1 randomised Serious no serious no serious Serious none 20 20 - SMD 0.98 higher LOW CRITICAL
b
trials risk of inconsistency indirectness imprecision (0.32 higher to 1.64
a
bias higher)
WOMAC pain- up to and including 13 weeks follow up (Iannitti 2012)
b
trials risk of inconsistency indirectness imprecision (0.29 lower to 0.96
a
bias higher)
WOMAC pain - more than 13 weeks follow up (Iannitti 2012)
b
a
bias higher)
Update 2014
WOMAC function- up to and including 13 weeks follow up (Iannitti 2012)
1 randomised Serious no serious no serious Very serious none 20 20 - SMD 0.06 lower VERY CRITICAL
b
trials risk of inconsistency indirectness imprecision (0.68 lower to 0.56 LOW
a
bias higher)
WOMAC function - more than 13 weeks follow up (Iannitti 2012)
b
a
bias higher)
WOMAC stiffness- up to and including 13 weeks follow up (Iannitti 2012)
1 randomised Serious no serious no serious Serious none 20 20 - SMD 0.22 lower LOW CRITICAL
b
a
bias higher)
WOMAC stiffness- more than 13 weeks follow up (Iannitti 2012)
1 randomised Serious no serious no serious Serious none 20 20 - SMD 0.14 lower LOW CRITICAL
b
a
bias higher)
363
Osteoarthritis
Table 243: Clinical evidence profile: Knee OA-Hyruan (unlicensed product) vs Hyalart (unlicensed product)
Importan
Quality
No of Risk of Imprecisio Other Relative ce
Design Inconsistency Indirectness Hyruan Hyal Absolute
studies bias n considerations (95% CI)
Adverse events at injection site-- number of knees (up to and including 13 weeks) – Swelling (Lee 2006)
a
1 randomised serious no serious no serious very none 25/93 29/89 RR 0.82 (0.53 59 fewer per 1000 IMPORTA
b
trials inconsistency indirectness serious (26.9%) (32.6% to 1.29) (from 153 fewer to 94 VERY NT
) more) LOW
Adverse events at injection site-- number of knees (up to and including 13 weeks) – Tenderness (Lee 2006)
a b
1 randomised serious no serious no serious serious none 45/73 45/73 RR 1 (0.77 to 0 fewer per 1000 (from IMPORTA
trials inconsistency indirectness (61.6%) (61.6% 1.29) 142 fewer to 179 more) LOW NT
Update 2014
)
Table 244: Clinical evidence profile: Knee OA- Go-On (unlicensed product) vs Hyalgan (licensed product)
Importan
Other Quality
No of Risk of Relative ce
Design Inconsistency Indirectness Imprecision consideratio Go-On Hylagan Absolute
studies bias (95% CI)
ns
VAS pain-26 weeks (Berenbaum 2012)
1 randomised No No serious No serious No serious None 217 209 - SMD 0.27 lower (0.46 HIGH CRITICAL
trials serious inconsistency indirectness imprecision lower to 0.07 lower)
risk of
bias
WOMAC pain-26 weeks (Berenbaum 2012)
364
Osteoarthritis

Importan
Other Quality
ns
risk of
bias
WOMAC function-26 weeks (Berenbaum 2012)
risk of
bias
WOMAC stiffness-26 weeks (Berenbaum 2012)
Update 2014
risk of
bias
Lequesne index-26 weeks (Berenbaum 2012)
risk of
bias
OARSI- OMERACT responder-26 weeks (Berenbaum 2012)
1 randomised No No serious No serious serious None 159/217 122/209 RR 1.26 152 more per 1000 MODER IMPORTA
b
trials serious inconsistency indirectness imprecision (73.3%) (58.4%) (1.09 TO (from 53 more to 257 ATE NT
risk of 1.44) more)
bias
Patient Global Assessment (VAS)-26 weeks (Berenbaum 2012)
1 randomised No No serious No serious No serious None 217 209 - SMD 0.16 (0.03 lower HIGH IMPORTA
trials serious inconsistency indirectness imprecision to 0.35 more) NT
risk of
bias
Patient Global assessment- up to 13 weeks follow up post-injection (Arensi 2006)
365
Osteoarthritis

Importan
Other Quality
ns
b
1 randomised very no serious no serious very serious none 13/20 13/20 RR 1 (0.63 0 fewer per 1000 (from IMPORTA
a
trials serious inconsistency indirectness (65%) (65%) to 1.58) 240 fewer to 377 more) VERY NT
LOW
Number of patients reporting adverse events- 26 weeks (Berenbaum 2012)
1 randomised No No serious no serious serious None 74/223 75/213 RR 0.94 21 fewer per 1000 MODER IMPORTA
b
trials serious inconsistency indirectness imprecision (33.2%) (35.2%) (0.73 to (from 95 fewer to 77 ATE NT
risk of 1.22) more)
bias
Number of patients discontinued due to adverse events- 26 weeks (Berenbaum 2012)
b
1 randomised No No serious no serious very serious None 3/223 4/213 RR 0.72 5 fewer (from 16 fewer LOW IMPORTA
Update 2014
trials serious inconsistency indirectness (1.3%) (1.9%) (0.16 to to 41 more) NT
risk of 3.16)
bias
Table 245: Clinical evidence profile: Knee OA- SLM-10 (unlicensed product) vs Artz (unlicensed product)
Importan
Quality
Design Inconsistency Indirectness Imprecision SLM-10 Artz Absolute
Patient global assessment (number of patients better or much better)-up to 13 weeks follow up post-injection (Kawabata 1993)
a
1 randomise serious no serious no serious no serious none 56/82 53/74 RR 0.95 36 fewer per 1000 IMPORTA
d trials inconsistency indirectness imprecision (68.3%) (71.6% (0.78 to (from 158 fewer to MODERAT NT
) 1.17) 122 more) E
Safety: local adverse events related to study drug resulting in withdrawals- up to 13 weeks follow up post-injection (Kawabata 1993)
a b
1 randomise serious no serious no serious very serious none 1/85 2/79 RR 0.46 14 fewer per 1000 IMPORTA
366
Osteoarthritis
d trials inconsistency indirectness (1.2%) (2.5%)

(0.04 to (from 24 fewer to VERY LOW NT
5.03) 102 more)
Safety: local adverse events no specific causal relationship to study drug and continuation in trial- up to 13 weeks follow up post-injection (Kawabata 1993)
a b
1 randomise serious no serious no serious very serious none 1/85 1/79 RR 0.93 1 fewer per 1000 IMPORTA
d trials inconsistency indirectness (1.2%) (1.3%) (0.06 to (from 12 fewer to VERY LOW NT
14.61) 172 more)
Table 246: Clinical evidence profile: Knee OA- Zeel compositum (unlicensed product) vs Hyalart (unlicensed product)
Importan
Quality
Design Inconsistency Indirectness Imprecision Zeel compositum Hyalart Absolute
Update 2014
Patient global: number of patients with noticeable improvements in symptoms (up to 13 weeks post-injection) (Nahler 1998)
a
1 randomise serious no serious no serious no serious none 48/55 53/57 RR 0.94 56 fewer per IMPORTA
d trials inconsistency indirectness imprecision (87.3%) (93%) (0.83 to 1000 (from 158 MODERAT NT
1.06) fewer to 56 E
more)
Patient assessment of improvement (0-100 mm VAS) (Better indicated by lower values) (up to 13 weeks post-injection) (Nahler 1998)
a b
1 randomise serious no serious no serious serious none 55 57 - SMD 0.16 lower IMPORTA
d trials inconsistency indirectness (0.53 lower to LOW NT
0.21 higher)
Patient assessment of tolerance (0-100 mm VAS) (Better indicated by lower values) (up to 13 weeks post-injection) (Nahler 1998)
a b
1 randomise serious no serious no serious serious none 55 57 - SMD 0.16 lower IMPORTA
d trials inconsistency indirectness (0.53 lower to LOW NT
0.21 higher)
367
Osteoarthritis
Table 247: Clinical evidence profile: Knee OA- Hylan GF 20 (licensed product): 1 x 6mL injection vs 1 x 4mL injection vs 2 x 4mL injections vs 3 x 4mL
injections vs 3 x 2mL injections
Importanc
Quality
No of Risk of Other Hylan Hylan Relative e
studies bias considerations GF 20 GF 20 (95% CI)
Adverse events related to device- 1 x 6mL - 1 x 6mL vs 1 x 4mL- more than 13 weeks follow up post-injection (Conrozier 2009)
1 randomised very no serious no serious very none 2/20 4/21 RR 0.52 91 fewer per 1000 IMPORTAN
a b
trials serious inconsistency indirectness serious (10%) (19%) (0.11 to (from 170 fewer to VERY T
2.56) 297 more) LOW
Adverse events related to device- 1 x 6mL - 1 x 6mL vs 2 x 4mL- more than 13 weeks follow up post-injection(Conrozier 2009)
a b
trials serious inconsistency indirectness serious (10%) (10.5%) (0.15 to (from 89 fewer to 535 VERY T
6.08) more) LOW
Update 2014
a b
1.46) 138 more) LOW
1 randomised very no serious no serious very none 2/20 2/20 RR 1 (0.16 0 fewer per 1000 IMPORTAN
a b
trials serious inconsistency indirectness serious (10%) (10%) to 6.42) (from 84 fewer to 542 VERY T
more) LOW
1 randomised very no serious no serious very none 4/21 2/19 RR 1.81 85 more per 1000 IMPORTAN
a b
trials serious inconsistency indirectness serious (19%) (10.5%) (0.37 to (from 66 fewer to 819 VERY T
8.78) more) LOW
a b
1.92) 276 more) LOW
1 randomised very no serious no serious very none 4/21 2/20 RR 1.9 (0.39 90 more per 1000 IMPORTAN
a b
trials serious inconsistency indirectness serious (19%) (10%) to 9.28) (from 61 fewer to 828 VERY T
more) LOW
368
Osteoarthritis

Importanc
Quality
No of Risk of Other Hylan Hylan Relative e
studies bias considerations GF 20 GF 20 (95% CI)
a b
trials serious inconsistency indirectness serious (10.5%) (30%) (0.08 to (from 276 fewer to VERY T
1.53) 159 more) LOW
Adverse events related to device- 2 x 4mL - 2 x 4mL vs 3 x 2 mL- more than 13 weeks follow up post-injection (Conrozier 2009)
1 randomised very no serious no serious very none 2/19 2/20 RR 1.05 5 more per 1000 IMPORTAN
a b
trials serious inconsistency indirectness serious (10.5%) (10%) (0.16 to (from 84 fewer to 574 VERY T
6.74) more) LOW
1 randomised very no serious no serious very none 6/20 2/20 RR 3 (0.69 200 more per 1000 IMPORTAN
a b
trials serious inconsistency indirectness serious (30%) (10%) to 13.12) (from 31 fewer to VERY T
Update 2014
1000 more) LOW
Table 248: Clinical evidence profile: Knee OA- Hyalgan (licensed product): 5 injections vs 3 injections
Qualit Importan
No of Risk of Imprecisio Other Hyalgan 5 Hyalgan 3 Relative y ce
studies bias n considerations injections injections (95% CI)
Patient global (number of patients assessing response as satisfactory) - more than 13 weeks post-injection (Karras 2001)
a b
1 randomised serious no serious no serious serious none 49/73 68/86 RR 0.85 (0.7 119 fewer per 1000 IMPORTA
trials inconsistency indirectness (67.1%) (79.1%) to 1.03) (from 237 fewer to 24 LOW NT
more)
369
Osteoarthritis
Table 249: Clinical evidence profile: Knee OA- Orthovisc (licensed product): 4 injections vs 3 injections
Importan
Quality
No of Risk of Imprecisio Other Orthovisc 4 Orthovisc 3 Relative ce
studies bias n considerations injections injections (95% CI)
Patient global assessment (0 to 100 mm VAS; change from baseline) - up to 13 weeks post-injection (Better indicated by lower values) (Neustadt 2005a)
a b
1 randomised serious no serious no serious serious none 115 107 - SMD 0.3 lower (0.56 IMPORTA
trials inconsistency indirectness to 0.03 lower) LOW NT
Patient global assessment (0 to 100 mm VAS; change from baseline) - more than 13 weeks post-injection (Better indicated by lower values) (Neustadt 2005a)
a b
1 randomised serious no serious no serious serious none 115 107 - SMD 0.24 lower (0.51 IMPORTA
trials inconsistency indirectness lower to 0.02 higher) LOW NT
Safety: number of patients with skin adverse events - more than 13 weeks post-injection (Neustadt 2005a)
Update 2014
a
1 randomised serious no serious no serious very none 3/128 1/119 RR 2.79 15 more per 1000 IMPORTA
b
trials inconsistency indirectness serious (2.3%) (0.8%) (0.29 to (from 6 fewer to 214 VERY NT
26.45) more) LOW
Table 250: Clinical evidence profile: Knee OA- HA- no product specified (unlicensed product): 6 injections vs 3 injections
Relativ Importan
Quality
No of Risk of Other e ce
Design Inconsistency Indirectness Imprecision 6 injections 3 injections Absolute
studies bias considerations (95%
CI)
WOMAC pain (less than 13 weeks follow up post injection) (Better indicated by lower values) (Petrella 2006)
a
1 randomise serious no serious no serious no serious none 53 53 - SMD 0.01 higher CRITICAL
d trials inconsistency indirectness imprecision (0.37 lower to MODERAT
0.39 higher) E
370
Osteoarthritis
Relativ Importan
Quality
No of Risk of Other e ce
Design Inconsistency Indirectness Imprecision 6 injections 3 injections Absolute
studies bias considerations (95%
CI)
WOMAC stiffness (less than 13 weeks follow up post injection) (Better indicated by lower values) (Petrella 2006)
a b
1 randomise serious no serious no serious serious none 53 53 - SMD 0.22 lower CRITICAL
d trials inconsistency indirectness (0.6 lower to LOW
0.16 higher)
WOMAC function (less than 13 weeks follow up post injection) (Better indicated by lower values) (Petrella 2006)
a b
1 randomise serious no serious no serious serious none 53 53 - SMD 0.15 higher CRITICAL
d trials inconsistency indirectness (0.24 lower to LOW
Update 2014
0.53 higher)
Patient Global Assessment (less than 13 weeks follow up post injection) (Better indicated by lower values) (Petrella 2006)
a
1 randomise serious no serious no serious no serious none 53 53 - SMD 1.28 higher IMPORTA
d trials inconsistency indirectness imprecision (0.86 to 1.7 MODERAT NT
higher) E
SF36 - Physical function (less than 13 weeks follow up post injection) (Better indicated by lower values) (Petrella 2006)
1
1 randomise serious no serious no serious no serious none 53 53 - SMD 0.08 higher IMPORTA
d trials inconsistency indirectness imprecision (0.3 lower to MODERAT NT
0.46 higher) E
SF36- Vitality (less than 13 weeks follow up post injection) (Better indicated by lower values) (Petrella 2006)
a
1 randomise serious no serious no serious no serious none 53 53 - SMD 0.07 lower IMPORTA
d trials inconsistency indirectness imprecision (0.45 lower to MODERAT NT
0.31 higher) E
371
Osteoarthritis
Hip OA
Table 251: Clinical evidence profile: Hip OA- Hyalgan (licensed product) vs Saline
No of
Quality assessment Effect
patients Quali Importa
ty nce
No of Risk of Imprecisi Other Hyalg Salin Relative
studies bias on considerations an e (95% CI)
Pain on walking, mm VAS at 13 weeks (Better indicated by lower values) Qvitsgaard 2006
a b
1 randomised serious no serious no serious serious none 33 36 - SMD 0.25 lower (0.73 lower to CRITICAL
trials inconsistency indirectness 0.22 higher) LOW
OARSI responder criteria at 28 days Qvitsgaard 2006
a b
1 randomised serious no serious no serious serious none 17/33 16/36 RR 1.16 (0.71 71 more per 1000 (from 129 IMPORT
Update 2014
trials inconsistency indirectness (51.5 (44.4 to 1.9) fewer to 400 more) LOW ANT
%) %)
Table 252: Clinical evidence profile: Hip OA- Durolane(licensed product) vs Saline
No of
patients Importan
Quality
ce
No of Risk of Imprecisi Other Durolan Salin Relative Absolut
Design Inconsistency Indirectness
studies bias on considerations e e (95% CI) e
Adverse events (post injection flare) at < 13 weeks Atchia 2011
b
1 randomised very no serious no serious serious none 4/19 0/19 RR 9 (0.52 to - IMPORTA
a
trials serious inconsistency indirectness (21.1%) (0%) 156.41) VERY NT
LOW
372
Osteoarthritis
Table 253: Clinical evidence profile: Hip OA: Hyalgan (licensed product) vs Methylprednisolone

Quali Importa
ty nce
No of Risk of Imprecisi Other Hyalg Methylpredniso Relative
studies bias on considerations an lone (95% CI)
Pain on walking, mm VAS at 13 weeks (Better indicated by lower values) Qvitsgaard 2006
a b
1 randomised serious no serious no serious serious none 33 32 - SMD 0.09 lower (0.58 lower LOW CRITICAL
Update 2014
trials inconsistency indirectness to 0.39 higher)
OARSI responder criteria at 28 days Qvitsgaard 2006
a b
1 randomised serious no serious no serious serious none 17/33 21/32 RR 0.78 (0.52 144 fewer per 1000 (from IMPORT
trials inconsistency indirectness (51.5 (65.6%) to 1.19) 315 fewer to 125 more) LOW ANT
%)
Table 254: Clinical evidence profile: Hip OA- Hylan G-F 20 (licensed product) vs Methylprednisolone

Importanc
Quality
e
No of Risk of Other Hylan Methylprednisolon Relative
studies bias considerations G-F 20 e (95% CI)
WOMAC pain at 26 weeks (Better indicated by lower values) Spitzer 2010
373
Osteoarthritis

Importanc
Quality
e
No of Risk of Other Hylan Methylprednisolon Relative
studies bias considerations G-F 20 e (95% CI)
a
trials inconsistency indirectness imprecision (0.32 lower to MODER
0.12 higher) ATE
WOMAC function at 26 weeks (Better indicated by lower values) Spitzer 2010
a
1 randomised serious no serious no serious no serious none 156 156 - SMD 0.07lower CRITICAL
trials inconsistency indirectness imprecision (0.29 lower to MODER
0.15 higher) ATE
WOMAC stiffness at 26 weeks (Better indicated by lower values) Spitzer 2010
Update 2014
a
1 randomised serious no serious no serious no serious none 156 156 - SMD 0.06 lower MODER CRITICAL
trials inconsistency indirectness imprecision (0.28 lower to ATE
0.16 higher)
Patients global assessment at 26 weeks (Better indicated by lower values) Spitzer 2010
a
1 randomised serious no serious no serious no serious none 156 156 - SMD 0.13 lower MODER IMPORTAN
trials inconsistency indirectness imprecision (0.35 lower to ATE T
0.09 higher)
Local adverse events at 26 weeks Spitzer 2010
a b
1 randomised serious no serious no serious very serious none 21/156 27/156 RR 0.78 35 fewer per IMPORTAN
trials inconsistency indirectness (14%) (17.4%) (0.46 to 1000 (from 91 LOW T
1.32) fewer to 63
more)
374
Osteoarthritis
Table 255: Clinical evidence profile: Hip OA-Durolane (licensed product) vs Methylprednisolone

Importa
Quality
nce
No of Risk of Imprecisi Other Durola Methylpredniso Relative Absolu
studies bias on considerations ne lone (95% CI) te
Adverse events(Post injection flare) at < 13 weeks Atchia 2011
b
1 randomised very no serious no serious serious None 4/19 0/20 RR 9.45 (0.54 to - IMPORT
a
trials serious inconsistency indirectness (21.1% (0%) 164.49) VERY ANT
) LOW
Update 2014
Table 256: Clinical evidence profile: Hip OA- Durolane (licensed product) vs Standard care

Importan
Quality
ce
No of Risk of Imprecisi Other Durola Standard Relative Absolu
studies bias on considerations ne care (95% CI) te
Adverse events(Post injection flare) Atchia 2011
b
1 randomised very no serious no serious serious None 4/19 0/20 RR 9.45 (0.54 to - IMPORTA
a
trials serious inconsistency indirectness (21.1%) (0%) 164.49) VERY NT
LOW
375
Osteoarthritis
Table 257: Clinical evidence profile: Hip OA- Adant (unlicensed product) vs Saline
No of
patients Importa
Quality
nce
No of Other Adan Salin Relative
studies considerations t e (95% CI)
WOMAC pain at 3 months (Better indicated by lower values) Richette 2009
1 randomised no serious no serious no serious no serious None 42 43 - SMD 0.05 lower (0.47 CRITICAL
trials risk of bias inconsistency indirectness imprecision lower to 0.38 higher) HIGH
WOMAC function at 3 months (Better indicated by lower values) Richette 2009
1 randomised no serious no serious no serious no serious None 42 43 - SMD 0.05 lower (0.47 CRITICAL
WOMAC stiffness at 3 months (Better indicated by lower values) Richette 2009
a
1 randomised no serious no serious no serious serious none 42 43 - SMD 0.32 higher (0.11 CRITICAL
Update 2014
trials risk of bias inconsistency indirectness lower to 0.75 higher) MODERA
TE
Pain VAS at 3 months (Better indicated by lower values) Richette 2009
1 randomised no serious no serious no serious no serious None 42 43 - SMD 0.05 higher (0.38 CRITICAL
Patient's global assessment at 3 months (Better indicated by lower values) Richette 2009
1 randomised no serious no serious no serious no serious None 42 43 - SMD 0.06 lower (0.49 IMPORT
trials risk of bias inconsistency indirectness imprecision lower to 0.36 higher) HIGH ANT
Local adverse events at 3 months Richette 2009
a
1 randomised no serious no serious no serious very serious None 5/42 2/43 RR 2.56 (0.53 73 more per 1000 (from 22 IMPORT
trials risk of bias inconsistency indirectness (11.9 (4.7% to 12.47) fewer to 533 more) LOW ANT
%) )
OARSI responders at 3 months Richette 2009
a
1 randomised no serious no serious no serious very serious None 14/42 14/43 RR 1.02 (0.56 7 more per 1000 (from 143 IMPORT
trials risk of bias inconsistency indirectness (33.3 (32.6 to 1.88) fewer to 287 more) LOW ANT
%) %)
376
Osteoarthritis
Table 258: Clinical evidence profile: Hip OA- Ostenil (licensed product) vs Hylan G-F 20

Importa
Quality
nce
No of Risk of Imprecisi Other Oste Hylan G- Relative
studies bias on considerations nil F 20 (95% CI)
Pain VAS - Pain VAS at 3 months (Better indicated by lower values) Tikiz 2005
1 randomised very no serious no serious very none 25 18 - SMD 0.04 lower (0.64 lower to CRITICAL
a b
trials serious inconsistency indirectness serious 0.57 higher) VERY
LOW
Update 2014
Pain VAS - Pain VAS at 6 months (Better indicated by lower values) Tikiz 2005
b
1 randomised very no serious no serious serious none 25 18 - SMD 0.43 higher (0.18 lower to CRITICAL
a
trials serious inconsistency indirectness 1.05 higher) VERY
LOW
Local adverse events Tikiz 2005
b
1 randomised very no serious no serious serious none 3/32 3/24 RR 0.75 (0.17 31 fewer per 1000 (from 104 IMPORT
a
trials serious inconsistency indirectness (9.4% (12.5%) to 3.4) fewer to 300 more) VERY ANT
) LOW
377
Osteoarthritis
Ankle OA
Table 259: Clinical evidence profile: Ankle OA-Hyalgan (licensed product) vs Saline
No of
patients Importa
Quality
nce
No of Risk of Other Hyalg Salin Relative
studies bias considerations an e (95% CI)
EQ5D- Domain: no problem at 6 months Salk 2006
b
1 randomised very no serious no serious serious None 7/9 2/8 RR 3.11 (0.89 527 more per 1000 (from 28 IMPORT
a
trials serious inconsistency indirectness (77.8 (25% to 10.86) fewer to 1000 more) VERY ANT
%) ) LOW
Update 2014
EQ5D- Domain: some problem at 6 months Salk 2006
1 randomised very no serious no serious no serious None 2/9 6/8 RR 0.3 (0.08 525 fewer per 1000 (from 690 IMPORT
a
trials serious inconsistency indirectness imprecision (22.2 (75% to 1.07) fewer to 53 more) LOW ANT
%) )
EQ5D- Domain: unable to perform at 6 months Salk 2006
1 randomised very no serious no serious no serious none 0/9 0/8 not pooled not pooled IMPORT
a
trials serious inconsistency indirectness imprecision (0%) (0%) LOW ANT
Local adverse events at 6 months Salk 2006; Cohen 2008
b
2 randomised very no serious no serious serious none 3/25 2/22 RR 1.33 (0.29 30 more per 1000 (from 65 IMPORT
a
trials serious inconsistency indirectness (12%) (9.1 to 6.06) fewer to 460 more) VERY ANT
%) LOW
378
Osteoarthritis
Table 260: Clinical evidence profile: Ankle OA- Supartz (unlicensed product) vs Saline
No of
patients Importa
Quality
nce
No of Risk of Other Supar Salin Relative
studies bias considerations tz e (95% CI)
Pain VAS at 12 weeks (Better indicated by lower values) Degroot 2012
a b
1 randomised serious no serious no serious serious none 35 21 - SMD 0.28 higher (0.27 lower CRITICAL
trials inconsistency indirectness to 0.82 higher) LOW
Local adverse events at 12 weeks Degroot 2012
a
1 randomised serious no serious no serious no serious none 0/35 0/21 not not pooled IMPORT
trials inconsistency indirectness imprecision (0%) (0%) pooled MODERA ANT
TE
Update 2014
Table 261: Clinical evidence profile: Ankle OA- Adant (unlicensed product) vs Exercise
No of
patients Importa
Quality
nce
No of Risk of Other Ada Exerci Relative
studies bias considerations nt se (95% CI)
Pain on activity, VAS at 1 year (Better indicated by lower values) Karatosun 2008
b
1 randomised very no serious no serious serious none 15 15 - SMD 0.38 lower (1.1 lower to CRITICAL
a
LOW
Pain at rest, VAS at 1 year (Better indicated by lower values) Karatosun 2008
2
1 randomised very no serious no serious serious none 15 15 - SMD 0.25 lower (0.97 lower CRITICAL
a
trials serious inconsistency indirectness to 0.47 higher) VERY
379
Osteoarthritis
No of
patients Importa
Quality
nce
No of Risk of Other Ada Exerci Relative
studies bias considerations nt se (95% CI)
LOW
Local adverse events at 1 year Karatosun 2008
1 randomised very no serious no serious no serious none 0/15 0/15 not not pooled IMPORT
1
trials serious inconsistency indirectness imprecision (0%) (0%) pooled LOW ANT
Update 2014
Base of thumb OA
Table 262: Clinical evidence profile: Base of thumb OA- Synvisc (licensed product) vs Saline
No of
patients Qualit Importan
y ce
No of Risk of Other Synvis Salin Relative
studies bias considerations c e (95% CI)
Local adverse events at >13 weeks Hayworth 2008
1 randomised very no serious no serious no serious none 0/20 0/18 not not IMPORTA
a
trials serious inconsistency indirectness imprecision (0%) (0%) pooled pooled LOW NT
380
Osteoarthritis
Table 263: Clinical evidence profile: Base of thumb OA- Ostenil (licensed product) vs Triamcinolone

Importanc
Quality
e
No of Risk of Other Osteni Triamcinolon Relative
studies bias considerations l e (95% CI)
Pain VAS - Pain VAS at 3 months (Better indicated by lower values): Bahadir 2009
b
a
higher) LOW
Pain VAS - Pain VAS at 1 year (Better indicated by lower values): Bahadir 2009
b
a
higher) LOW
Update 2014
Local adverse events at 1 year: Bahadir 2009
1 randomised very no serious no serious no serious none 0/20 0/20 not not pooled IMPORTAN
a
trials serious inconsistency indirectness imprecision (0%) (0%) pooled LOW T
Table 264: Clinical evidence profile: Base of thumb OA- Orthovisc (licensed product) vs Methylprednisolone
Importa
Relativ Quality
nce
No of Risk of Other Orthovi Methylpredniso e
studies bias considerations sc lone (95%
CI)
Pain on activity, VAS - Pain on activity at 3 months (Better indicated by lower values) Stahl 2005
b
381
Osteoarthritis
Importa
Relativ Quality
nce
No of Risk of Other Orthovi Methylpredniso e
studies bias considerations sc lone (95%
CI)
a
LOW
Pain on activity, VAS - Pain on activity at 6 months (Better indicated by lower values) Stahl 2005
b
a
LOW
Pain at rest, VAS - Pain at rest at 3 months (Better indicated by lower values) Stahl 2005
b
Update 2014
a
LOW
Pain at rest, VAS - Pain at rest at 6 months (Better indicated by lower values) Stahl 2005
b
1 randomised very no serious no serious very serious none 27 25 - SMD 0 higher (0.54 CRITICAL
a
LOW
Local adverse events at 6 months Stahl 2005
1 randomised very no serious no serious no serious none 0/27 0/25 not not pooled IMPORT
a
trials serious inconsistency indirectness imprecision (0%) (0%) pooled LOW ANT
Table 265: Clinical evidence profile: Base of thumb OA- Synvisc (licensed product) vs Betamethasone
Quali Importan
ty ce
382
Osteoarthritis
No of Risk of Other Synvi Betamethas Relative

studies bias considerations sc one (95% CI)
Local adverse events at > 13 weeks Hayworth 2008
1 randomised very no serious no serious no serious none 0/20 0/22 not not IMPORTA
a
trials serious inconsistency indirectness imprecision (0%) (0%) pooled pooled LOW NT
First MTP joint OA
Table 266: Clinical evidence profile: First MTP joint OA- Synvisc (licensed product) vs Saline

Importanc
Quality
e
Update 2014
Design Inconsistency Indirectness Imprecision Synvisc Saline Absolute
SF-36 Physical component - SF36 Physical at 3 months (Better indicated by lower values) Munteanu 2011
a
1 randomised serious no serious no serious no serious none 75 76 - SMD 0.03 lower (0.35 IMPORTAN
trials inconsistency indirectness imprecision lower to 0.29 higher) MODERAT T
E
SF-36 Physical component - SF36 Physical at 6 months (Better indicated by lower values) Munteanu 2011
a
1 randomised serious no serious no serious no serious none 75 76 - SMD 0.08 higher IMPORTAN
trials inconsistency indirectness imprecision (0.24 lower to 0.4 MODERAT T
higher) E
SF-36 Mental component - SF36 Mental at 3 months (Better indicated by lower values) Munteanu 2011
a b
1 randomised serious no serious no serious serious none 75 76 - SMD 0.22 higher (0.1 IMPORTAN
trials inconsistency indirectness lower to 0.54 higher) LOW T
SF-36 Mental component - SF36 Mental at 6 months (Better indicated by lower values) Munteanu 2011
a
1 randomised serious no serious no serious no serious none 75 76 - SMD 0.09 higher IMPORTAN
trials inconsistency indirectness imprecision (0.23 lower to 0.41 MODERAT T
higher) E
383
Osteoarthritis

Importanc
Quality
e
Design Inconsistency Indirectness Imprecision Synvisc Saline Absolute
Patient's global assessment at 3 months Munteanu 2011
a b
1 randomised serious no serious no serious serious none 23/75 30/76 RR 0.78 (0.5 87 fewer per 1000 IMPORTAN
trials inconsistency indirectness (30.7% (39.5% to 1.21) (from 197 fewer to 83 LOW T
) ) more)
Patient's global assessment at 6 months Munteanu 2011
a b
1 randomised serious no serious no serious serious none 21/75 29/76 RR 0.73 103 fewer per 1000 IMPORTAN
trials inconsistency indirectness (28%) (38.2% (0.46 to (from 206 fewer to 61 LOW T
) 1.16) more)
Local adverse events at 6 months Munteanu 2011
Update 2014
a b
1 randomised serious no serious no serious serious none 19/73 32/74 RR 0.6 (0.38 173 fewer per 1000 IMPORTAN
trials inconsistency indirectness (26%) (43.2% to 0.96) (from 17 fewer to 268 LOW T
) fewer)
Table 267: Clinical evidence profile: First MTP joint OA- Ostenil (licensed product) vs Triamcinolone

Importa
Quality
nce
No of Risk of Imprecisi Other Osten Triamcinol Relative
studies bias on considerations il one (95% CI)
Pain on walking 20 m(VAS) at 3 months (Better indicated by lower values): Pons 2007
b
a
LOW
384
Osteoarthritis
Pain at rest/palpation at 3 months (Better indicated by lower values): Pons 2007

b
a
LOW
Responder rate (Pts achieving 20mm decrease in pain at rest/palpation) at 3 months: Pons 2007
Update 2014
b
1 randomised very no serious no serious serious none 11/17 9/19 RR 1.37 (0.76 175 more per 1000 (from 114 IMPORT
a
trials serious inconsistency indirectness (64.7 (47.4%) to 2.46) fewer to 692 more) VERY ANT
%) LOW
385
Osteoarthritis
Evidence from CG59:
Four studies comparing hyaluronans with a relevant comparator were included228,456,478,505. Three of
the studies compared hyaluronans with some form of conventional care456,228,478, and one study
compared hyaluronan with celecoxib and naproxen505.
However due to methodological limitations, the use of these papers was limited, and evidence
statements could not be made from them. Therefore, these papers have been excluded from the
guideline update – reasons for exclusion are summarised in Appendix K.
Update 2014
Additionally, an original cost-effectiveness analysis was conducted in CG59 which calculated the cost-
effectiveness of hyaluronans using three placebo (saline) controlled RCTs4,100,368 (included in the
original guideline review). WOMAC scores were taken from the RCTs and mapped onto EQ-5D using
the formula from Barton 200822. Only direct costs of the interventions were considered, assuming
one GP consultation per injection.
A summary of this CG59 analysis can be found in Appendix M. Evidence statements have not been
drafted for the CG59 analysis as this has not been updated in this guideline update, and more weight
was placed by the GDG on cost effectiveness and clinical evidence from the update guideline.
One study was identified with the relevant intervention285. This study was selectively excluded due to
a poor study design, lack of comparator, and non-UK setting. This study is summarised in Appendix H,
with reasons for exclusion given.
386
Osteoarthritis
Unit costs
Relevant unit costs are provided in Table 268 below to aid consideration of cost effectiveness.
The table below shows an example of the costs of some of the hyaluronan products available, and
also the cost of some steroid injection products for comparison.
Table 268: Unit cost of hyaluronan and steroid products

Number of Price
injections per
Product Description of contents Price per course course*
Hyaluronan products
Durolane Box containing 1 pre-filled 3ml syringe £199.17 1 £199
Box containing 3 pre-filled 2ml syringes (1
Euflexxa £195.00 3 £195
treatment)
Box containing 1 pre-filled 20mg/2ml 3 (could be
Fermathron £39.00 £117
syringe up to 5)
Orthovisc Box containing 1 pre-filled 2ml syringe £65.00 3 £195
Box containing 1 pre-filled 20mg/2ml
Ostenil £33.96 3 £102
syringe
Box containing 1 pre-filled dual
RenehaVis £112.00 Up to 3 £336
chambered 1.4ml syringe
Update 2014
Box containing 1 pre-filled 20mg/2ml
Suplasyn £35.50 3 £106.50
syringe
Box containing 1 pre-filled 20mg/2ml 3 (could be
Synocrom £30.00 £90
syringe up to 5)
Synolis Box containing 1 pre-filled 2ml syringe £75.00 3 £225
Synvisc Box containing 3 pre-filled 2ml syringes (1
£205.00 3 £205
(Hylan G-F20) treatment)
Synvisc ONE
Box containing 1 pre-filled 6ml syringe £205.00 1 £205
(Hylan G-F20)
Steroid injection products
40mg/1ml suspension for injection vials £3.44 1 (2 if £3.44
Methylprednisolo required)
80mg/2ml suspension for injection vials £6.18 £6.18
ne acetate 1 (2 if
120mg/3ml suspension for injection vials £8.96 £8.96
required)
Triamcinolone 40mg/1ml suspension for injection Repeated if
£7.45 necessary £7.45
acetonide vials
* Depending on the number of injections recommended per course (e.g. Durolane and Synvisc ONE are single dose
preparations, whereas Fermarthron requires 3 injections).
Source of prices: Drug Tariff; http://www.ppa.org.uk/edt/June_2012/mindex.htm (note: the table is not an exhaustive
list of all products available). Number of injection per course are from the BNF for steroids, and the internet for
hyaluronans.
387
Osteoarthritis
Economic considerations
As well as the cost of the product, the time needed by the professional to administer the injection is
also an additional cost, and the more injections needed then the higher the cost.
As an estimate, the average GP surgery consultation costs around £36.h The injection may be given
by a specialist such as a rheumatologist, instead of a GP, which will probably be associated with a
higher cost.
The possibility of adverse events from the hyaluronan injections have also been highlighted in the
cinical review. These would have treatment costs as well as health consequences associated with
them.
Clinical
10.2.4.1 OA Knee- licensed hyaluronans
Hyaluronan vs Placebo
Hyalgan
One study with 177 people with osteoarthritis of the knee suggested that Hyalgan and placebo may
Update 2014
be similarly effective in reducing WOMAC pain at follow up less of than 13 weeks [LOW].
Two studies with 372 people with osteoarthritis of the knee suggested that Hyalgan and placebo may
be similarly effective in reducing WOMAC pain at follow-up of more than 13 weeks [LOW].
Three studies with 482 people with osteoarthritis of the knee suggested that there may be fewer
people with painful injections or injection site pain in the placebo group compared to the Hyalgan
group at follow-up of more than 13 weeks, although there was some uncertainty surrounding this
effect [LOW].
Hylan GF20
One study with 94 people with osteoarthritis of the knee suggested that Hylan GF20 and placebo
may be similarly effective in reducing global pain measured on a VAS scale at follow up less of than
13 weeks [MODERATE].
Four studies with 233 people with osteoarthritis of the knee suggested that Hylan GF20 may be
clinically more effective than placebo in improving WOMAC pain at follow up less of than 13 weeks,
although there was some uncertainty surrounding this effect [VERY LOW].
One study with 30 people with osteoarthritis of the knee suggested that multiple injections of Hylan
GF20 may be more clinically effective than placebo in improving WOMAC pain at follow-up of more
than 13 weeks, although there was some uncertainty surrounding this effect [LOW].
One study with 243 people with osteoarthritis of the knee suggested that single injections of Hylan
GF20 may not be more clinically effective than placebo in improving WOMAC pain at follow-up of
more than 13 weeks, although there was some uncertainty surrounding this effect [LOW].
h
Source: Unit costs of health and social care, PSSRU (2011). This cost includes direct care staff costs (without qualifications).
388
Osteoarthritis
Five studies with 417 people with osteoarthritis of the knee suggested that there may be fewer
patients with local reactions in the placebo group compared to people in the Hylan GF20 group at a
follow up of less than 13 weeks [VERY LOW].
One study with 52 people with osteoarthritis of the knee suggested that there may be fewer patients
with local reactions in the placebo group compared to people in the Hylan GF20 group at a follow up
of more than 13 week, although there was some uncertainty surrounding this effect s [VERY LOW].
Orthovisc
Six studies with 449 people with osteoarthritis of the knee suggested that Orthovisc may be clinically
more effective than placebo at reducing WOMAC pain at follow up less of than 13 weeks, although
there was some uncertainty surrounding this effect [VERY LOW].
Five studies with 408 people with osteoarthritis of the knee suggested that Orthovisc may be
clinically more effective than placebo at reducing WOMAC pain at follow-up of more than 13 weeks,
Three studies with 719 people with osteoarthritis of the knee suggested that there may be fewer
people with adverse events (local skin rash) in the Orthovisc group compared to people in the
placebo or arthroscopy (alone) groups at follow up of more than 13 weeks, although there was some
uncertainty surrounding this effect [VERY LOW].
BioHy
One study with 588 people with osteoarthritis of the knee suggested that BioHy and placebo may be
Update 2014
similarly effective in reducing WOMAC pain at follow-up of more than 13 weeks [MODERATE].
One study with 588 people with osteoarthritis of the knee suggested that and placebo may be
similarly effective at improving health related quality of life (using SF 36) at follow-up of more than
One study with 59 people with osteoarthritis of the knee suggested that there were fewer adverse
events (injection site pain) in people in the placebo group compared to people in the BioHy group at
follow-up of more than 13 weeks, although there was some uncertainty surrounding this effect
[LOW].
Durolane
Two studies with 692 people with osteoarthritis of the knee suggested that Durolane and placebo
may be similarly effective in improving WOMAC pain at follow up less of than 13 weeks [MODERATE].
One study with 346 people with osteoarthritis of the knee suggested that Durolane and placebo may
be similarly effective in improving WOMAC pain at follow-up of more than 13 weeks [MODERATE].
One study with 347 people with osteoarthritis of the knee suggested there were fewer adverse
events related to the injection in the Durolane group compared to the placebo group at follow-up of
more than 13 weeks, although there was some uncertainty surrounding this effect [LOW].
Suplasyn
One study with 53 people with osteoarthritis of the knee suggested that Suplasyn and placebo may
be similarly effective in reducing WOMAC pain at follow up of less than 13 weeks [MODERATE].
Hyaluronan vs NSAIDs
Hyalgan
389
Osteoarthritis
One study with 240 people with knee osteoarthritis suggested that Hyalgan and Naproxen may be
similarly effective in the reduction of pain measured on the VAS scale at follow up of less than 13
weeks [MODERATE].
One study with 216 people with knee osteoarthritis suggested that Hyalgan and Naproxen may be
similarly effective in the reduction of pain measured on the VAS scale at follow up of more than 13
weeks follow up [MODERATE].
One study with 327 people with knee osteoarthritis showed that there may have been fewer people
with injection site pain in the Naproxen group compared to the Hyalgan group at follow up of more
than 13 weeks [MODERATE].
Hylan GF20
One study with 57 people with knee osteorarthritis suggested that Hylan GF20 and NSAID may be
similarly effective in reducing pain measured on a VAS scale at follow up of less than 13 weeks [VERY
LOW ].
One study with 58 people with knee osteoarthritis suggested that Hylan GF20 and NSAID may be
similarly effective in reducing pain measured on a VAS scale at follow up of more than 13 weeks
[VERY LOW].
One study with 108 people with knee osteoarthritis suggested that Hylan GF20 and NSAID may be
similarly effective in reducing pain measured with a WOMAC scale at follow up of less than 13 weeks
[LOW].
Update 2014
One study with 102 people with knee osteoarthritis suggested that fewer people had local adverse
reactions in the NSAID group compared to people in the Hylan GF20 at follow up of less than 13
weeks [VERY LOW].
Suplasyn
One study with 54 people with knee osteoarthritis suggested that suplasyn and NSAID may be
similarly effective in the reduction of pain measured on the WOMAC scale at follow up of less than
Hyaluronan vs Triamcinolone
Hylan GF20
One study with 215 people with knee osteoarthritis suggested that Hylan GF20 and triamcinolone
may be similarly effective in reducing pain measured on a WOMAC scale at follow up of less than 13
weeks [LOW].
One study with 215 people with knee osteoarthritis suggested that Hylan GF20 and triamcinolone
may be similarly effective in reducting pain measured on a WOMAC scale at follow up of more than
13 weeks [LOW].
Durolane
One study with 60 people with knee osteoarthritis suggested that durolane and triamcinolone may
be similarly effective in reducing pain measured on a VAS scale at follow up of less than 13 weeks
[VERY LOW].
Ostenil
390
Osteoarthritis
One study with 42 people with osteoarthritis of the knee suggested that ostenil and placebo may be
similarly effective in the reduction of pain measured on a VAS scale as follow up of less than 13
weeks [VERY LOW].
Hyaluronan vs steroid
Hyalgan
No study included in this review reported critical outcomes of global pain (VAS or WOMAC), quality
of life or adverse events.
Orthovisc
One study with 55 people with knee osteoarthritis suggested that people may have fewer skin
adverse events in the methylprednisolone group compared to people who took orthovisc at follow
up of more than 13 weeks, although there was some uncertainty surrounding this effect [VERY LOW].
One study with 55 people with knee osteoarthritis suggested orthovisc and methyprednislone may
be similarly effective in the number of patients reporting knee pain at follow up of more than 13
weeks [VERY LOW].
Orthovisc vs betamethasone
No study in this comparison reported critical outcomes of global pain (VAS or WOMAC), quality of life
or adverse events.
Update 2014
Hyaluronan vs physiotherapy
Hylan GF20
One study with 40 people with knee osteoarthritis suggested that Hylan GF20 may be clinically more
effective than physiotherapy in reduction in pain measured on a WOMAC scale at follow up of less
than 13 weeks, but there was some uncertainty [VERY LOW].
One study with 40 people with osteoarthritis of the knee suggested that Hylan GF 20 may be more
clinically effective than physiotherapy at reducing pain measured on a WOMAC scale at follow up of
more than 13 weeks [VERY LOW].
One study with 40 people with osteoarthritis of the knee suggested that Hylan GF20 and
physiotherapy may be similarly effective at improving quality of life measured with SF36 (physical
functioning domain) at follow up of less than 13 weeks [VERY LOW].
One study with 40 people with osteoarthritis of the knee suggested that Hylan GF20 and
physiotherapy may be similarly effective at improving quality of life measured with SF36 (physical
functioning domain) at follow up of more than 13 weeks [VERY LOW].
Orthovisc
One study with 40 people with osteoarthritis of the knee suggested that orthovisc and physical
therapy may be similarly effective at reducing pain measured on the WOMAC scale at follow up of
less than 13 weeks [VERY LOW].
One study with 40 people with osteoarthritis of the knee suggested that orthovisc may be more
clinically effective than physical therapy in the reduction of pain measured on the WOMAC scale at
follow up of more than 13 weeks, but there was some uncertainty [LOW].
391
Osteoarthritis
One study with 40 people with osteoarthritis of the knee suggested that physical therapy may be
more clinically effective than orthovisc in improving quality of life measured by SF36 (physical
functioning domain) at follow up of less than 13 weeks, but there was some uncertainty [VERY LOW].
One study with 40 people with osteoarthritis of the knee suggested that physical therapy may be
more clinically effective than orthovisc in improving quality of life measured by SF36 (physical
functioning domain) at follow up of more than 13 weeks, although there was some uncertainty
surrounding this effect [VERY LOW ].
Hyaluronan vs conventional treatment
Hyalgan
One study with 36 people with osteoarthritis of the knee suggested that Hyalgan may be more
clinically effective than conventional treatment in reducing pain measured on a VAS scale at follow
up of more than 13 weeks, but there was some uncertainty [VERY LOW].
One study with 36 people with osteoarthritis of the knee suggested that Hyalgan and conventional
treatment may be similarly effective at improving quality of life as measured by AIMS at follow up of
more than 13 weeks [VERY LOW].
Hyaluronan vs appropriate treatment
Hylan GF 20
One study with 497 people with osteoarthritis of the knee suggested that Hylan GF 20 may be more
Update 2014
clinically effective than appropriate care in reducing pain measured on the WOMAC scale at follow
up of more than 13 weeks, although there was some uncertainty surrounding this effect [LOW ].
10.2.4.2 OA Knee-unlicensed hyaluronans
Hyaluronan vs placebo
Artz
Three studies with 507 people with osteoarthritis of the knee showed that Artz and placebo may be
similarly effective at reducing pain measured on the VAS scale at follow up of less than 13 weeks
[HIGH].
Two studies with 312 people with osteoarthritis of the knee showed that Artz and placebo may be
similarly effective at reducing pain measured on the VAS scale at follow up of more than 13 weeks
[MODERATE].
One study with 223 people with osteoarthritis of the knee suggested that artz and placebo may be
similarly effective at reducing pain measured on the WOMAC scale at follow up of less than 13 weeks
[VERY LOW].
Adant
No study included in this comparison reported critical outcomes of global pain (VAS or WOMAC),
quality of life or adverse events.
NRD-101
392
Osteoarthritis
One study with 174 people with osteoarthritis of the knee showed that NRD-101 and placebo may be
similarly effective at reducing pain measured on the VAS scale at follow up of more than 13 weeks
[HIGH ].
One study with 216 people with osteoarthritis of the knee suggested that fewer people who received
oral placebo and placebo injection reported knee pain during or after injection compared to NRD-101
at follow up of more than 13 weeks, although there was some uncertainty surrounding this effect
[LOW].
Hyaluronan vs steroid
Artz
One study with 51 people with osteoarthritis of the knee suggested that artz and corticosteroids are
similarly effective in the reduction of pain measured on a VAS scale as follow up of less than 13
weeks [VERY LOW].
One study with 51 people with osteoarthritis of the knee suggested that artz and corticosteroids are
similarly effective in the reduction of pain measured on a VAS scale as follow up of more than 13
weeks [VERY LOW].
Hyaluronan vs exercise
Artz
One study with 87 people with osteoarthritis of the knee showed that artz and exercise may be
Update 2014
similarly effective at reducing pain measured on a VAS scale as follow up of more than 13 weeks
[LOW].
10.2.4.3 OA Knee: Hyaluronan product vs another Hyaluronan product- unlicensed or licensed
Hyalgan vs Hylan GF20
One study with 54 people with osteoarthritis of the knee suggested that people receiving hyalgan
injections may have fewer local reactions (acute inflammation and pain) than people receiving Hylan
GF20 at follow up of less than 13 weeks [VERY LOW].
BioHy vs Hylan GF20
One study with 321 people with osteoarthritis of the knee showed that BioHy and Hylan GF20 are
similarly effective in the reduction of pain as measured with the WOMAC scale at follow up of less
than 13 weeks [HIGH].
Orthovisc vs Hylan GF20
Three studies with 121 people with osteoarthritis of the knee suggested that Orthovisc and Hylan
GF20 may be similarly effective in the reduction of pain as measured with the WOMAC scale at
follow up of less than 13 weeks [VERY LOW].
Two studies with 81 people with osteoarthritis of the knee suggested that Orthovisc and Hylan GF20
may be similarly effective in the reduction of pain as measured with the WOMAC scale at follow up
of more than 13 weeks [VERY LOW].
One study with 40 people with osteoarthritis of the knee showed that Hylan GF20 may be more
clinically effective than Orthovisc at improving quality of life (physical functioning domain) measured
with SF36 at follow up of less than 13 weeks [LOW].
393
Osteoarthritis
One study with 40 people with osteoarthritis of the knee suggested that Hylan GF20 may be more
clinically effective than Orthovisc at improving quality of life (physical functioning domain) measured
with SF36 at follow up of more than 13 weeks, but there was some uncertainty [VERY LOW].
Two studies with 92 people with osteoarthritis of the knee suggested that there may be fewer local
adverse events in the hylan GF20 group compared to the orthovisc group at follow up of more than
13 weeks [VERY LOW].
Hylan GF20 vs Sinovial
One study with 380 people with osteoarthritis of the knee suggested that Hylan GF 20 and Sinovial
may be similarly effective in reducing WOMAC pain at follow up of less than 13 weeks [MODERATE].
One study with 381 people with osteoarthritis of the knee suggested that Hylan GF 20 and Sinovial
and are similarly effective in the reduction of WOMAC pain at follow up of more than 13 weeks
[MODERTE]
One study with 381 people with osteoarthritis of the knee suggested that people had fewer adverse
events relating to injections in the Synovial group compared to the Hylan GF 20 group at follow up of
more than 13 weeks, although there was some uncertainty surrounding this effect [VERY LOW].
Adant vs hyalgan
One study with 49 people with osteoarthritis of the knee suggested that people had fewer painful
injections in the Hyalan group compared to the Adant group at follow up of less than 13 weeks [VERY
LOW].
Update 2014
Fermathron vs hyalart
One study with 233 people with osteoarthritis of the knee suggested that fermathron and hylart
were similarly effective in the reduction in pain measured on the VAS scale at follow up of less than
13 weeks [HIGH].
Hylan GF 20 vs Variofill
One study with 20 people with bilateral knee OA (40 knees) showed that Hylan GF 20 and Variofill
may be similarly effective in improving VAS pain at follow up of less than 13 weeks [VERY LOW]
One study with 20 people with bilateral knee OA (40 knees) suggested that Variofill may be clinically
more effective in improving VAS pain than Hylan GF 20 at follow up of more than 13 weeks, but there
was some uncertainty [LOW]
One study with 20 people with bilateral knee OA (40 knees) showed that Hylan GF 20 and Variofill
may be similarly effective in improving WOMAC pain at follow up of less than 13 weeks [LOW]
One study with 20 people with bilateral knee OA (40 knees) suggested that Variofill may be clinically
more effective at improving WOMAC pain than Hylan GF 20 at follow up of more than 13 weeks, but
there was some uncertainty [LOW]
Hyruan vs Hyal
One study which assessed 182 people with osteoarthritis of the knee suggested that there may be no
clinically important difference between Hyruan and Hyal in the number of knees with swelling at
injection site at follow up of less than 13 weeks [Very low quality].
One study which assessed 146 people with osteoarthritis of the knee suggested that there may be no
clinically important difference between Hyruan and Hyal in the number of knees with tenderness at
injection site at follow up of less than 13 weeks [Low quality].
394
Osteoarthritis
Go-on vs Hyalgan
One study with 426 people with osteoarthritis of the knee showed that Go-on and Hyalgan may be
similarly effective at improving VAS pain at follow up of more than 13 weeks [HIGH]
One study with 426 people with osteoarthritis of the knee showed that Go-on and Hyalgan may be
similarly effective at improving WOMAC pain at follow up of more than 13 weeks [HIGH]
One study with 436 people with osteoarthritis of the knee showed that there may be no clinically
important difference between Go-on and Hyalgan in the total number of people reporting adverse
events at follow up of more than 12 weeks [MODERATE].
One study with 436 people with osteoarthritis of the knee suggested that there may be fewer
patients who discontinue treatment due to adverse events in the Go-on group compared to the
Hyalgan group at follow up of more than 12 weeks, although there was some uncertainty
surrounding this effect [LOW].
SLM-10 vs artz
One study with 164 people with osteoarthritis of the knee suggested that there may be fewer local
adverse events related to study drug resulting in withdrawals in the SLM-10 group compared to the
artz group at follow up of less than 13 weeks, although there was some uncertainty surrounding this
effect [VERY LOW].
One study with 164 people with osteoarthritis of the knee suggested that there may be no difference
between SLM-10 and Artz in the number of local adverse events with no specific relationship to the
Update 2014
study drug at follow up of less than 13 weeks [VERY LOW].
Zeel compositum vs hylart
10.2.4.4 OA knee: Hyaluronan product vs different doses of same Hyaluronan product
Hylagan: 5 injections vs 3 injections
Hylan GF 20: 1 x6mL injection vs 1 x 4mL injection vs 2 x 4mL injection vs 3 x 4mL injection
One study with 41 people in the intervention groups of interest who had osteoarthritis of the knee
suggested that fewer people had adverse events related to the injection in the 1 x 6mL injection
group compared to the 1 x 4mL injection group at follow up of more than 13 weeks, although there
was some uncertainty surrounding this effect [VERY LOW].
suggested that there was no difference between 1 x 6mL injection group and 2 x 4mL injection group
in the number of people that experienced adverse event related to the injection [VERY LOW].
suggested that fewer people had adverse events related to the injection in the 1 x 6mL injection
group compared to the 3 x 4mL injection group at follow up of more than 13 weeks, although there
was some uncertainty surrounding this effect [VERY LOW ].
395
Osteoarthritis
suggested that there was no difference between 1 x 6mL injection and 3 x 2mL injection in the
number of people that experienced adverse event related to the injection at follow up of more than
13 weeks [VERY LOW].
suggested that fewer people experienced adverse events related to the injection in the 1 x4mL
injection group compared to the 2 x 4mL injection group at follow up of more than 13 weeks,
suggested that fewer people had adverse events in the 1 x 4mL injections group compared to the 3 x
4mL injection group at follow up of more than 13 weeks, although there was some uncertainty
surrounding this effect [VERY LOW ].
suggested that fewer people receiving 3 x 2mL injection had fewer adverse events than people
receiving the 1 x 4mL injection at follow up of more than 13 weeks, although there was some
uncertainty surrounding this effect [VERY LOW ].
suggested that fewer people receiving the 2 x 4mL injection experienced adverse events relating to
the injection compared to people receiving 3 x 4mL injections at follow up of more than 13 weeks,
Update 2014
suggested that there was no difference between people receiving 2 x 4mL injections or the 3 x 2mL
injection in the number of people experiencing adverse events related to the injection at follow up
of more than 13 weeks [VERY LOW].
suggested that there may be fewer people who experienced adverse events relating to the injection
in the 3 x 2mL injection group compared to the 3 x 4mL injection group at follow up of more than 13
weeks, although there was some uncertainty surrounding this effect [VERY LOW].
Orthovisc: 4 injections vs 3 injections
One study with 247 people with osteoarthritis of the knee suggested that there may be fewer
patients with skin adverse events in the group who had 3 injections of orthovisc compared to the
group who had 4 injections of orthovisc at follow up of more than 13 weeks [VERY LOW].
HA (no formulation stated): 6 injections vs 3 injections
One study with 106 people with osteoarthritis of the knee showed that there may be no clinically
important difference between HA and placebo in the reduction of pain as measured on the WOMAC
scale at follow up of less than 13 weeks [MODERATE].
One study with 106 people with osteoarthritis of the knee suggested that HA and placebo may be
similarly effective in improving quality of life as measured by SF36 (physical function domain) at
follow up of less than 13 weeks [MODERATE ].
One study with 106 people with osteoarthritis of the knee suggested that HA and placebo may be
similarly effective in improving quality of life as measured by SF36 (vitality domain) at follow up of
less than 13 weeks [MODERATE].
Hyaluronan (no product stated): 6 injections vs 3 injections
396
Osteoarthritis
One study with 106 people with osteoarthritis of the knee suggested that 6 injection and 3 injections
of hyaluronan were similarly effective in the reduction in WOMAC pain at follow up of less than 13
weeks [MODERATE].
of hyaluronan are similarly effective in the improvement of SF36 (physical function) at follow up of
less than 13 weeks [MODERATE].
of hyaluronan may be similarly effective in the improvement of SF36 (vitality) at follow up of less
than 13 weeks [MODERATE].
10.2.4.5 OA Hip- licensed hyaluronans
Hyaluronan vs Saline
Hyalgan
One study with 69 people with osteoarthritis of the hip suggested that Hyalgan and saline may be
similarly effective in reducing pain on walking measured on the visual analogue scale at follow up less
of than 13 weeks [LOW].
Durolane
Update 2014
One study with 38 people with osteoarthritis of the hip suggested that people may have fewer
adverse events in the saline group compared to Durolane with respect to adverse event profile at
follow up less of than 13 weeks, although there was some uncertainty surrounding this effect [VERY
LOW].
Hyaluronan vs Steroid
Hyalgan
One study with 65 people with osteoarthritis of the hip suggested that Hyalgan and
methylprednisolone may be similarly effective in reducing pain on walking measured on the visual
analogue scale at follow up less of than 13 weeks [LOW].
Hylan G-F 20
One study with 312 people with osteoarthritis of the hip showed that Hylan G-F 20 and
methylprednisolone may be similarly effective at reducing pain measured on the WOMAC scale at
follow up greater than 13 weeks [MODERATE].
One study with 312 people with osteoarthritis of the hip suggested that there may be no difference
between Hylan G-F 20 and methylprednisolone with respect to adverse event profile at follow up
greater than 13 weeks [LOW].
Durolane (licensed)
One study with 39 people with osteoarthritis of the hip suggested that people may experience fewer
adverse events in the methylprednisolone group compared to the Durolane group with respect to
adverse event profile at follow up less than 13 weeks, although there was some uncertainty
397
Osteoarthritis
Hyaluronan vs Standard care
Durolane
One study with 39 people with osteoarthritis of the hip suggested that standard care may be
clinically more effective than Durolane with respect to adverse profile at follow up less than 13
weeks, but there was some uncertainty [VERY LOW]
10.2.4.6 OA Hip- unlicensed hyaluronans
Adant
One study with 85 people with osteoarthritis of the hip suggested that Adant and saline may be
simllarly effective in reducing pain measured on the WOMAC scale at follow up less of than 13 weeks
[HIGH].
One study with 85 people with osteoarthritis of the hip suggested that Adant and saline may be
similarly effective in reducing pain measured on the visual analogue scale at follow up less of than 13
weeks [HIGH].
One study with 85 people with osteoarthritis of the hip suggested that people may have fewer
events in the saline group may be clinically more effective than Adant with respect to adverse event
Update 2014
profile at follow up less of than 13 weeks [High quality].
10.2.4.7 OA Hip: Hyaluronan vs Hyaluronan (licensed preparations)
Ostenil vs Hylan G-F 20
One study with 43 people with osteoarthritis of the hip suggested that Ostenil and Hylan G-F 20 may
be similarly effective in reducing pain measured on the visual analogue scale at follow up less than 13
weeks [VERY LOW].
One study with 43 people with osteoarthritis of the hip suggested that Ostenil and Hylan G-F 20 may
be similarly effective in reducing pain measured on the visual analogue scale at follow up greater
than 13 weeks [VERY LOW].
One study with 56 people with osteoarthritis of the hip suggested people may have fewer adverse
events in the Ostenil group compared to the Hylan G-F 20 group with respect to adverse event
profile at follow up greater than 13 weeks [VERY LOW ].
10.2.4.8 OA Ankle- licensed hyaluronans
Hyalgan
One study with 17 people with osteoarthritis of the ankle suggested that Hyalgan may be clinically
more effective than saline in improving quality of life measured by EQ5D (domain: no problem) at
follow up greater than 13 weeks, but there was some uncertainty [VERY LOW ].
398
Osteoarthritis
One study with 17 people with osteoarthritis of the ankle suggested Hyalgan and saline may be
similarly effective in improving quality of life measured by EQ5D (domain: some problem) at follow
up greater than 13 week, although there was some uncertainty surrounding this effect s [LOW].
One study with 17 people with osteoarthritis of the ankle suggested that Hyalgan and saline may be
similarly effective in improving quality of life measured by EQ5D (domain: unable to perform) at
follow up greater than 13 weeks [LOW].
Two studies with 47 people with osteoarthritis of the ankle suggested that saline may be clinically
more effective than Hyalgan with respect to adverse event profile at follow up greater than 13
weeks, although there was some uncertainty surrounding this effect [VERY LOW].
10.2.4.9 OA Ankle- unlicensed hyaluronans
Supartz
One study with 56 people with osteoarthritis of the ankle suggested that Supartz and saline may be
similarly effective in reducing pain measured on the visual analogue scale at follow up less than 13
weeks [LOW].
One study with 56 people with osteoarthritis of the ankle suggested that there may be no clinically
important difference between Supartz and saline with respect to adverse event profile at follow up
less than 13 weeks [LOW].
Hyaluronan vs Exercise
Update 2014
Adant
One study with 30 people with osteoarthritis of the ankle suggested that Adant and exercise may be
similarly effective in reducing pain on activity measured on the visual analogue scale at follow
greater than 13 weeks [VERY LOW].
One study with 30 people with osteoarthritis of the ankle suggested that Adant and exercise may be
similarly effective in reducing pain at rest measured on the visual analogue scale at follow greater
than 13 weeks [VERY LOW].
One study with 30 people with osteoarthritis of the ankle showed that there may be no clinically
important difference between Adant and exercise with respect to adverse event profile at follow
greater than 13 weeks [VERY LOW].
10.2.4.10 OA Base of thumb- licensed hyaluronans
Synvisc
One study with 38 people with osteoarthritis of the base of thumb showed that there may be no
clinically important difference between Synvisc and saline with respect to adverse event profile at
Ostenil vs Triamcinolone
399
Osteoarthritis
One study with 40 people with osteoarthritis of the base of thumb suggested that triamcinolone may
be clinically more effective than Ostenil in reducing pain measured on the visual analogue scale at
follow up less than 13 weeks, but there was some uncertainty [VERY LOW].
One study with 40 people with osteoarthritis of the base of thumb suggested that triamcinolone may
be clinically more effective than Ostenil in reducing pain measured on the visual analogue scale at
follow up of greater than 13 weeks, but there was some uncertainty [VERY LOW].
One study with 40 people with osteoarthritis of the base of thumb suggested that there may be no
difference between Ostenil and triamcinolone with respect to adverse event profile at follow greater
than 13 weeks [LOW].
Orthovisc vs Methylprednisolone
One study with 52 people with osteoarthritis of the base of thumb suggested that Orthovisc and
methylprednisolone may be similarly effectivein reducing pain on activity measured on the visual
analogue scale at follow up less than 13 weeks [VERY LOW].
methylprednisolone may be similarly effective in reducing pain on activity measured on the visual
analogue scale at follow up greater than 13 weeks [VERY LOW].
methylprednisolone may be similarly effective in reducing pain at rest measured on the visual
analogue scale at follow up less than 13 weeks [VERY LOW].
Update 2014
methylprednisolone may be similarly effective in reducing pain at rest measured on the visual
analogue scale at follow up greater than 13 weeks [VERY LOW].
difference between Orthovisc and methylprednisolone with respect to adverse event profile at
Synvisc vs Betamethasone
difference between Synvisc and betamethasone with respect to adverse event profile at follow up
greater than 13 weeks[Low quality].
10.2.4.11 OA first MTP joint- licensed hyaluronans
Synvisc
One study with 151 people with osteoarthritis of the first metatarsophalangeal joint suggested that
Synvisc and saline may be similarly effective in improving quality of life measured by the physical
component of SF36 at follow up less than 13 weeks[MODERATE].
Synvisc and saline may be similarly effective in improving quality of life measured by the physical
component of SF36 at follow up greater than 13 weeks [MODERATE].
Synvisc and saline may be similarly effective in improving quality of life measured by the mental
component of SF36 at follow up less than 13 weeks [LOW].
400
Osteoarthritis
Synvisc and saline may be similarly effective in improving quality of life measured by the mental
component of SF36 at follow up greater than 13 weeks [MODERATE].
people may have fewer adverse events in the Synvisc group compared to the saline group with
respect to adverse event profile at follow up greater than 13 weeks, but there was some uncertainty
[LOW].
Ostenil vs Triamcinolone
Ostenil may be clinically more effective than triamcinolone in reducing pain on walking 20 metres
measured on the visual analogue scale at follow up less than 13 weeks, but there was some
uncertainty [VERY LOW].
Ostenil and triamcinolone may be similarly effective in reducing pain at rest or palpation measured
on the visual analogue scale at follow up less than 13 weeks [VERY LOW].
Economic
Update 2014
34.Do not offer intra-articular hyaluronan injections for the management of

Recommendations
The GDG considered that pain measured on WOMAC or a visual analogue
Relative values of scale (VAS), function, quality of life and adverse events profile to be the
different critical outcomes for decision-making. Other important outcomes were
outcomes stiffness, structure modification, the OMERACT OARSI responder criteria and
the patient’s global assessment.
Trade off between The GDG considered the comparison of hyaluronan injections to placebo to
clinical benefits be the most appropriate comparator to judge clinical effectiveness and
and harms adverse events. Results were presented stratified by joint type and data was
available on knee, hip, ankle, base of thumb and great toe joints. The vast
majority of the data related to injections of the knee. Results were also
presented separately for those hyaluronan injections which are licenced in
the UK.
In looking at interventions appropriate controls are needed the GDG

considered the evidence for the efficacy of a given therapy, the primary
comparison for decision making involved looking at active therapies versus
placebo, and in the case of device studies versus sham control. They then
also considered other comparators where placebo or shams were not
available or inappropriate, such as when looking at toxicity and cost
effectiveness.
401
Osteoarthritis
The GDG understand and were aware of the considerable effect size of
contextual response in clinical trials and in practice for all therapies. Where
possible they tried to discern the specific treatment efficacy element that
relates to the treatment rather than contextual response. Where such trials
exist as to allow for the effective measurement of contextual response they
must form the primary comparator for decision making, to ensure we are
recording a therapy with a scientific treatment response. The GDG therefore
believe that saline is the appropriate comparator to elicit the specific
treatment efficacy for hyaluronans injections.
The GDG considered that the benefits of reduction in pain would be balanced
by the potential for adverse events/local reactions to the injection. The
number of injections required would also need to be considered.
The GDG noted that any degree of structure modification should be taken as
clinically important, thus the MID chosen for structural modification
outcomes was the line of no effect or zero. However, the relative lack of
data,inconsistent effects on structural modification and radiological method
of measurement of structure modification were noted and it was the critical
outcomes that guided the GDG decision making in this area
Knee OA
Licensed HA injections
Clinically important reduction in pain compared to placebo was

demonstrated for Hylan G-F20 on WOMAC scales at up to three months. At
over three months clinically important reductions in pain where shown when
multiple injections were used, this effect was not demonstrated for single
injections. Clinically important reduction in pain compared to placebo was
demonstrated for Orthovisc on the WOMAC pain scale at all time points.
However all these effects were surrounded by uncertainty and the quality
ranged from low to very low. No clinically important difference was
Update 2014
demonstrated over placebo on any pain scale at any time point for Durolane,
Hyalgan, BioHy and Suplasyn.
Quality of life data comparing HA injections with placebo was only available
for BioHy. No clinically important difference was demonstrated over placebo.
Hyalgan and Hyalan G-F20 both demonstrated higher rates of local adverse
reactions/pain at injection sites compared to placebo.
Unlicensed HA injections
No clinically important difference was demonstrated over placebo on any

pain scale at any time point for Artz and NRD-101.
No quality of life data was available on the comparison of unlicensed

hyaluronan injections compared to placebo.
NRD-101 demonstrated higher rates of pain during injection compared to

placebo
Hip OA
402
Osteoarthritis
Licensed hyaluronan injections

pain scale at any point for Hyalgan
No quality of life data was available on the comparison of licenced

hyaluronan injections compared to placebo
Durolane demonstrated rates of higher local adverse events than placebo
Unlicensed hyaluronan injections

pain scale at any point for Adant

Adant demonstrated rates of higher adverse events than placebo
Ankle OA
Licensed hyaluronan injections
No pain data was available on the comparison of licenced hyaluronan

injections compared to placebo
Clinically important improvement in the EQ5D domains of no problem and

some problem were demonstrated for Hyalgan over placebo, although there
was uncertainty surrounding the effects and the quality ranged from low to
very low
Hyalgan demonstrated rates of higher local adverse events than placebo
Unlicensed hyaluronan injections
Update 2014
pain scale at any point for Supartz

No adverse event data was available on the comparison of unlicensed

Base of thumb OA
Data available for the critical outcomes of pain, quality of life and adverse
events compared to placebo suggested there was no clinically important
difference in adverse events of the licensed hyaluronan Synvisc versus
placebo.
Base of thumb OA
Data available for the critical outcomes of pain, quality of life and adverse
events compared to placebo suggested there was no clinically important
difference in quality of life of the licenced hyaluronan Synvisc versus placebo.
403
Osteoarthritis
Economic An economic analysis from the previous guideline looked at the cost-
considerations effectiveness of hyaluronan injections compared with placebo (saline). This
found that hyaluronans were unlikely to be cost effective, as the incremental
cost-effectiveness ratios were outside of the £20,000 per QALY threshold.
This analysis was rated as having potentially serious limitations. As no costs
of placebo were included in the analysis, this could be interpreted as a
comparison with usual care, using placebo controlled trials.It is widely
accepted that large pragmatic randomised trials are the best study design on
which to base an economic evaluation, as this will capture the cost-
effectiveness of an intervention as it would be used in practice, compared to
what is currently standard care or in addition/as an adjunct to standard care.
The cost-effectiveness of hyaluronans versus placebo is not of interest, since
we are interested in the benefits and opportunity costs that would occur in
practice.
However an intervention must first be shown to have a clinical benefit, and

the best comparator to prove this would be a placebo or sham where
possible in order to identify the magnitude of effect over and above the
contextual/placebo response. Only if effect has been proven above
placebo/sham, should cost effectiveness evidence be considered. Saline is
considered to be the appropriate placebo for hyaluronan injections to elicit
the treatment efficacy.
One study was identified from the update search as potentially includable285.
However it was rated as having potentially serious/very serious limitations
and the GDG felt it should be excluded. Reasons include; poor study design,
lack of comparator, and non-UK setting.
Given no economic evidence, some assessment of cost-effectiveness is

described below.
The incremental cost of Suplasyn for example versus no treatment would be

£214.50 (assuming 3 injections and 3 GP consultations for Suplasyn and no
Update 2014
costs for no treatment). At this incremental cost, a QALY of 0.0107 would be
needed to achieve an ICER of £20,000. Although the incremental QALY gain
for hyaluronans versus no treatment would be higher than that of
hyaluronans versus placebo (as placebo’s have a small effect), we do not
think it will reach the 0.0107 threshold, as those compared to placebo were
lower than 0.005 (see appendix M).
When we compare hyaluronans with steroids, the incremental cost of

suplasyn versus a steroid injection is £100.32 (as one course of suplasyn (3
injections) costs £106.50, and one course of steroids (1 injection but can
have more if necessary) costs £6.18. The healthcare professional cost of
administering the injections is not considered as this is common to both
interventions). At this incremental cost, a QALY of 0.005 would be needed to
achieve an ICER of £20,000. As the effectiveness of hyaluronans over saline is
roughly the same as that of hyaluronans over steroids according to the
clinical review, we can compare this QALY gain with those reported in the
CG59 analysis as a reference (see appendix M). We can see that the
incremental QALYs are generally lower than 0.005. It seems unlikely that
hyaluronans would be cost effective given these figures, particularly if more
expensive products are used – as they can vary in price significantly.
404
Osteoarthritis
The GDG felt that the clinical evidence was not strong enough to warrant a
positive recommendation as the evidence varied.
Had there been positive evidence on the effectiveness of hyaluronans, then

above are some examples of assessment of cost-effectiveness given the lack
of published cost effectiveness evidence. As mentioned above, cost
effectiveness evidence based on pragmatic trials are preferred, so the
comparators are steroids, and no treatment.
Based on these considerationsthe GDG concluded that hyaluronan injections

are not likely to be cost effective
Quality of Knee OA
evidence
Licensed preparations of hyaluronans
For hyalgan versus conventional treatment at less than 13 weeks follow up

the evidence was of very low quality.
For hylan GF 20 versus placebo at less than 13 weeks the evidence was of
very low quality and for Hylan GF 20 versus placebo at more than 13 weeks
the evidence was of low quality. For Hylan GF 20 versus physical therapy and
appropriate care the evidence was of very low quality at more than 13
weeks.
For orthovisc versus placebo at less than and more than 13 weeks follow up
the evidence was of very low quality. For orthovisc versus physical therapy at
long term follow the evidence was of low quality evidence)and for
improving quality of life at short and long term follow up the evidence was of
very low quality.
For Hyalgan versus placebo or NSAIDs, Hylan GF 20 versus NSAID or

triamcinolone, BioHy vs placebo, Durolane versus placebo or triamcinolone,
suplasyn versus placebo or NSAID, ostenil versus triamcinolone the evidence
Update 2014
was mostly of low and very low quality.
Unlicensed preparations of hyaluronans
For Artz versus placebo, steroid or exercise for any outcome the evidence
was of low and very low quality and for NRD_101 versus placebo the
evidence was of high quality.
The majority of studies comparing one HA product to another were relatively

small and there was generally only one study per comparison. The quality of
the evidence ranged from very low to high, depending on the comparison
and the study.
Four studies compared a different number of injections of the same or

different HA products. The studies were generally small and the results
imprecise, allocation concealment and blinding was not well reported in the
studies. The evidence was of very low, low and moderate quality and there
was generally no difference between the different number of injections of
HA products.
Hip OA
405
Osteoarthritis
The licensed HA products compared for Hip OA (Hylagan or Durolane vs

saline, Hyalgan, Hylan or Durolane vs methylprednisolone and Durolane vs
standard care) included evidence that was mostly low and very low quality.
The unlicensed HA product Adant was compared to saline (High and

moderate quality evidence) and Ostenil was compared to Hylan GF 20 (Very
low quality evidence).
Ankle OA
For Hyalgan vs saline, the evidence was of very low quality. Another study
compared the use of Supartz to saline in ankle OA, and the evidence was of
low and moderate quality. Another study compared adant to exercise and
the evidence was of very low quality.
Base of thumb OA
For Synvisc vs saline or betamethasone the evidence was of low quality. For
ostenil vs triamcinolone the evidence was very low and low quality and for
Orthovisc vs methylprednisolone it was very low and low quality.
1st metacarpal joint OA
Update 2014
For Synvisc vs saline or Ostenil vs triamcinolone for people with OA of the 1st
MTP joint the evidence was of very low, low and moderate quality.
Other The GDG noted the findings of the evidence review and in particular
considerations commented that the quality of the evidence that demonstrated a possible
benefit from the use of Hyalgan over placebo in improving pain in people
with OA of the knee was of low quality. They therefore felt that it would not
be appropriate to name a particular preparation within a recommendation
especially when the evidence for this product was of varying quality They
noted also that the increased adverse events profile associated with
injections versus placebo.
The GDG decided that the recommendation made in the original OA

guideline (CG59) remained valid for the NHS and as such chose not to
recommend the use of hyaluronans.
The GDG noted that evidence was absent in relation to whether there were
specific groups of people who may respond better to hyaluronan injections
than others and as such chose to make a research recommendation in this
area
The GDG agreed to draft a research recommendation on identification of

predictors of response to individual treatments in people with osteoarthritis.
For further details on research recommendations, see Appendix M.
406
Osteoarthritis
Referral for specialist services
11 Referral for specialist services

11.1 Referral criteria for surgery
Prosthetic joint replacement is the removal of articular surfaces from a painful joint and their
replacement with synthetic materials, usually metal and plastic (although a variety of surfaces are
now in widespread use including ceramic and metal). It has been successfully performed for over 40
years and is now one of the commonest planned surgical procedures performed. Over 120,000 are
performed annually in the UK accounting for 1% of the total healthcare budget. It is performed in
the vast majority of cases for pain which originates from the joint, limits the patient’s ability to
perform their normal daily activities, disturbs sleep and does not respond to non-surgical measures.
Joint replacement is very effective at relieving these symptoms and carries relatively low risk both in
terms of systemic complications and suboptimal outcomes for the joint itself. Joint replacement
allows a return to normal activity with many patients able to resume moderate levels of sporting
activity including golf, tennis and swimming.
Successful outcomes require:

 careful selection of patients most likely to benefit
 thorough preparation in terms of general health and information
 well performed anaesthesia and surgery
 appropriate rehabilitation and domestic support for the first few weeks
For most patients the additional risk of mortality as a consequence of surgery, compared to
continuing conservative treatment is small.The recovery from joint replacement is rapid with
patients commencing rehabilitation the day following surgery and normal activities within 6 – 12
weeks, although knee recovery may be slower than hip; 95% of hip and knee replacements would be
expected to continue functioning well into the second decade after surgery with the majority
providing lifelong pain free function. However, around one in five patients are not satisfied with their
joint replacements and a few do not get much improvement in pain following joint replacement.
Joint replacement is one of the most effective surgical procedures available with very few
contraindications. As a result the demand from patients for these treatments continues to rise along
with the confidence of surgeons to offer them to a wider range of patients in terms of age, disability
and co-morbidities.
11.1.2 Methodological introduction: indications for joint replacement

We looked for studies that investigated the indications for referring osteoarthritis patients for
total/partial joint replacement surgery. Due to the large volume of evidence, studies were excluded if
they used a mixed arthritis population of which <75% had osteoarthritis or if population was not
relevant to the UK.
Seven expert opinion papers1,91,128,213,276,329,367, 1 cross-sectional study227, 1 observational study121 and

1 observational-correlation study179 were found.
The 7 expert opinion papers consisted of surveys and consensus group findings from
rheumatologists, orthopaedic surgeons and other clinicians and their opinions of the indications for
referral for joint replacement surgery.
407
Osteoarthritis
The cross-sectional study227 studied patients suitable for toal knee arthroplasty (TKA) and assessed
their willingness to undergo TKA surgery. The observational study121 assessed criteria that surgeons
used as indications for total hip arthroplasty (THA) surgery. The observational-correlation study179
assessed the willingness of patients (from low-rate and high-rate surgery areas) to undergo
arthroplasty.
All studies are hierarchy level of evidence 3 or 4.
11.1.3 Methodological introduction: predictors of benefit and harm

We looked for studies that investigated the patient centred factors that predict benefits and harms
from osteoarthritis related surgery. Due to the large volume of evidence, studies were excluded if
they used a mixed arthritis population of which <75% had osteoarthritis or if population was not
relevant to the UK. Additionally, studies were categorised into groups of predictive factors and for
each category, the largest trials and those that covered each outcome of interest were included.
2 cohort studies (level 2+)58,333, 2 case-control studies (level 2+)9,426 and 20 case-series’ (level
3)61,104,107,135,137,164,168,177,211,217,221,222,237,266,300,303,386,394,407,423 were found focusing on factors that predict
the outcome of joint replacement surgery.
The 2 cohort studies58,333 were methodologically sound and differed with respect to osteoarthritis /
surgery site, trial size and follow-up time. The first cohort study58 investigated N=100 patients who
had either TKA or THR compared to N=46 controls, with a follow-up time of 6 months. The second
cohort study333 investigated N=184 patients who had THR compared to N=2960 controls, with a
follow-up time of 6 and 12 months.
The 2 case-control studies9,426 were methodologically sound and both assessed the effect of knee
replacement surgery on Knee Society Score and Survival of the prosthesis in obese and non-obese
patients.
11.1.4 Evidence statements: indications for joint replacement
Age
Four studies1,91,227,276 looked at the effect of age on indications for surgery in knee osteoarthritis
patients and found that age was associated with the decision to perform surgery.
Three studies121,276,367 looked at the effect of age on indications for surgery in hip osteoarthritis
patients and found that age was associated with the decision to perform surgery.
1 study 179 looked at the effect of age on indications for surgery in hip or knee osteoarthritis patients
and found that age was associated with the decision to perform surgery.
Table 269: Effect of gender on attitudes towards surgery for OA

Age outcome Reference Outcome / Effect size
Knee osteoarthritis
227
Patient’s willingness 1 cross-sectional study (N=26,046) OR per 10-year increase in age: 0.71,
to undergo surgery 95% CI 0.65 to 0.77.
Favours younger persons (more
willing)
276
Indication for surgery 1 study of expert opinions (N=378 Age >80 = neutral factor
orthopaedic surgeons) Age <50 = sway decision against
surgery for most surgeons
408
Osteoarthritis
Age outcome Reference Outcome / Effect size

91
Referral for surgery 1 study of expert opinions ( N=244 Age <55 years: 52% FP’s = less likely
Family Physicians and N=96 and 35% = more likely to refer
Rheumatologists)
Age >80 years: >70% of FPs who
treated more patients with severe
knee osteoarthritis = less likely to refer
1
Indications for surgery 1 study of expert opinions (N=13 experts) Age < 55 years: alternative surgical
procedures considered
Poor outcomes do not appear to be
related to age
Data for risk factors is insufficient for
age
Hip
121
Priority for surgery 1 observational study (N=74 patients, Aged ≥ 70 years: RR 1.43, 95% CI 1.02
N=8 surgeons) to 2.01.
Favours older age (Higher priority)
367
Decision to perform 1 study of expert opinions (N=125 Age = significantly associated
arthroplasty orthopaedic surgeons)
276
Indications for surgery 1 study of expert opinions (N=378 Age >80 = neutral factor
orthopaedic surgeons) Age <50 = sway decision against
surgery for most surgeons
Age >80 and < 2years to live as neutral
factors
Age <50, cachexia and alcohol abuse =
less likely
Hip or knee
Definite willingness to 1 observational-correlation OR 0.57 for 65-74 years of age vs 55-
179
undergo arthroplasty study (N=1027) 64 years of age, p=0.0008
Favours younger age (more willing)
Gender
Two studies91,227 looked at the effect of gender on indications for surgery in knee osteoarthritis
patients and found that gender was not associated with the decision to refer for surgery but was
associated with the patient’s willingness to undergo surgery.
One study121 looked at the effect of gender on indications for surgery in hip osteoarthritis patients
and found that gender was associated with priority to undergo surgery.
One study179 looked at the effect of gender on indications for surgery in hip or knee osteoarthritis
patients and found that gender was not associated with willingness to undergo surgery.
Gender outcome Reference Outcome / Effect size
Knee osteoarthritis
227
Patient’s willingness 1 cross-sectional study (N=26,046) OR 0.60, 95% CI 0.49 to 0.74
to undergo surgery Favours men (more willing)
91
Referral for surgery 1 study of expert opinions ( N=244 Age <55 years: 52% FP’s = less likely
Family Physicians and N=96 and 35% = more likely to refer
Rheumatologists)
Age >80 years: >70% of FPs who
409
Osteoarthritis
Gender outcome Reference Outcome / Effect size

treated more patients with severe
knee osteoarthritis = less likely to refer
Hip
121
Priority for surgery 1 observational study (N=74 patients, RR 1.41, 95% CI 1.03 to 1.91
N=8 surgeons) Favours women (Higher priority)
Hip or knee
Definite willingness to 1 observational-correlation No association
179
undergo arthroplasty study (N=1027)
Weight/BMI
Two studies 1,276 looked at the effect of weight on indications for surgery in knee osteoarthritis
patients and found that weight was associated with the decision against surgery.
Three studies121 213,276 looked at the effect of weight on indications for surgery in hip osteoarthritis
patients and found that obesity was associated with the decision against surgery in 2 studies but was
not associated with decision for surgery in 1 study.
Table 270: Effect of weight/BMI on attitudes towards surgery for OA

Weight / BMI
outcome Reference Outcome / Effect size
Knee osteoarthritis
276
Indication for surgery 1 study of expert opinions (N=378 Obesity = sway decision against
orthopaedic surgeons) surgery for most surgeons
1
Indications for surgery 1 study of expert opinions (N=13 experts) Obesity = possible contraindication
(higher mechanical failure rate)
Obese = similar to normal population
for reduction in pain and disability
Data for risk factors is insufficient for
weight
Hip
121
Priority for surgery 1 observational study (N=74 patients, Not associated with obesity (BMI >30)
N=8 surgeons)
276
Indications for surgery 1 study of expert opinions (N=378 Obesity = sway decision against
Obesity = neutral or sway slightly
against surgery
213
Appropriateness of 1 study of expert opinions (N=8 Severe obesity in Grade 3
surgery orthopaedic surgeons, N=8 GPs) osteoarthritis patients = surgery not
appropriate (for most surgeons) and
sometimes in Grade 1 or 2
osteoarthritis patients.
Weight more influential than
comorbidities
Hip or knee
Definite willingness to 1 observational-correlation OR 0.57 for 65-74 years of age vs 55-
179
undergo arthroplasty study (N=1027) 64 years of age, p=0.0008
Favours younger age (more willing)
410
Osteoarthritis
Smoking / Drugs / Alcohol
Three studies1,91,276 looked at the effect of smoking, drugs or alcohol on indications for surgery in
knee osteoarthritis patients. 2 studies found that drug and/or alcohol use was associated with the
decision against surgery, however 1 study found that smoking data was insufficient to make a
conclusion.
One study 276 looked at the effect of smoking, drugs or alcohol on indications for surgery in knee
osteoarthritis patients. 2 studies found that alcohol use was associated with the decision against
surgery.
Table 271: Effect of smoking/drugs/alcohol on attitudes towards surgery for OA

Smoking / drug /
alcohol outcome Reference Outcome / Effect size
Knee osteoarthritis
276
Indication for surgery 1 study of expert opinions (N=378 Alcohol use = sway decision against
91
Referral for surgery 1 study of expert opinions ( N=244 History of drug/alcohol abuse: >70% of
Family Physicians and N=96 FPs and rheumatologists who treated
Rheumatologists) more patients with severe knee
osteoarthritis = less likely to refer
1
Indications for surgery 1 study of expert opinions (N=13 experts) Data for risk factors is insufficient for
smoking
Hip
276
Indications for surgery 1 study of expert opinions (N=378 Alcohol use = sway decision against
Co-morbidities
Three studies1,91,276 looked at the effect of comorbidities on indications for surgery in knee
osteoarthritis patients. Overall, all 3 studies found that comorbidities were associated with the
decision against surgery.
Two studies213,276 looked at the effect of comorbidities on indications for surgery in hip osteoarthritis
patients. 1 study found that comorbidities were associated with the decision against surgery, in the
second study experts were not sure about the role of comorbidities.
Table 272: Effect of comorbidities on attitudes towards surgery in OA

Comorbidities
Knee osteoarthritis
276
Indication for surgery 1 study of expert opinions (N=378 Comorbidities = sway decision against
91
Referral for surgery 1 study of expert opinions ( N=244 patello-femoral arthritis, peripheral
Family Physicians and N=96 vascular disease and sometimes local
Rheumatologists) active skin infection = less likely to
refer
1
Indications for surgery 1 study of expert opinions (N=13 experts) Comorbidities associated with poor
outcomes. Comorbidities = local or
systemic infection and other medical
conditions that substantially increase
411
Osteoarthritis
Comorbidities
the risk of serious perioperative
complications or death
Hip
276
Indications for surgery 1 study of expert opinions (N=378 Comorbidities = sway decision against
Comorbidities = neutral or sway
slightly against surgery
213
Appropriateness of 1 study of expert opinions (N=8 Disagreement about role of
surgery orthopaedic surgeons, N=8 GPs) comorbidities; comorbidities not
useful in resolving uncertain
indications for surgery
Structural features
One study276 looked at structural features as indications for surgery in knee osteoarthritis patients
and found that destruction of joint space was an indication for surgery.
Four studies 121,367 276 128 looked at structural features as indications for surgery in hip osteoarthritis
patients. Overall, all 3 studies found that joint space damage / high x-ray scores were required as an
indicator for surgery. 1 study found bone quality was not an indication for surgery.
Table 273: Effect of structural features on attitudes to surgery for OA

Structural features
Knee osteoarthritis
276
Indication for surgery 1 study of expert opinions (N=378 Majority of joint space destroyed =
orthopaedic surgeons) indication
Hip
121
Priority for surgery 1 observational study (N=74 patients, Higher X-ray ratings (score of >9/15:
N=8 surgeons) RR 1.98, 95% CI 1.23 to 3.19)
Higher priority
367
decision to perform 1 study of expert opinions (N=125 Quality of the bone = no association
arthroplasty orthopaedic surgeons)
276
Indications for surgery 1 study of expert opinions (N=378 majority of joint space destroyed =
orthopaedic surgeons) indication for surgery
128
Indications for surgery 1 study of expert opinions (N=304 X-ray changes = not very important
orthopaedic surgeons, N=314 referring 50% JSN or total loss of joint space =
physicians) indicator
Symptoms, Function, Global assessment, QoL
Five studies 121,128,213,276,367 looked at osteoarthritis symptoms and function as indications for surgery
in hip osteoarthritis patients and found mixed results, however pain was found by most studies to be
an important requirement for surgery.
412
Osteoarthritis
Hip or Knee
One study179 looked at osteoarthritis symptoms as indications for surgery in hip or knee
osteoarthritis patients and found no association between WOMAC disease severity and willingness to
undergo surgery.
Table 274: Effect of symptoms, function and quality of life on attitudes to surgery for OA
Symptoms, Function
and QoL outcome Reference Outcome / Effect size
Knee osteoarthritis
Indication for 1 study of expert Indications:
276
surgery opinions (N=378 At least have severe daily pain and rest pain several
orthopaedic surgeons) days/week and transfer pain (eg. Standing up from a
sitting position) several days/week
Unable to walk more than 3 blocks.
Difficulty climbing stairs
Not require marked abnormalities on physical
examination - nearly normal or somewhat decreased
flexion and a stable knee joint can be consistent with TKA.
Referral for surgery 1 study of expert Pain not responsive to drug therapy = more likely to refer
91
opinions ( N=244 Walking limited to <1 block without pain = more likely to
Family Physicians and refer
N=96 Rheumatologists) Persistent non-weight-bearing knee pain, Night pain and
Limitations of active flexion or extension = more likely to
refer
Indications for 1 study of expert Indications = Radiographic evidence of joint damage,
1
surgery opinions (N=13 moderate to severe persistent pain or disability or both
experts) (not substantially relieved by an extended nonsurgical
management (usually includes trials of analgesic and
NSAIDs, physical therapy, use of walking aids, reduction in
physical activities that provoke discomfort).
Hip
121
Priority for surgery 1 observational study Higher priority = Pain distress (RR 1.91, 95% CI 1.43 to
(N=74 patients, N=8 2.56); Pain intensity (RR 1.91, 95% CI 1.43 to 2.56); Higher
surgeons) patient ratings of average pain distress (RR 1.57, 95% CI
1.13 to 2.19); Higher patient ratings of average pain
disruption (RR 1.41, 95% CI 1.04 to 1.92); AIMS total > 50
(RR: 1.75, 95% CI 1.324 to 2.48).
Not associated wit priority = Patient pain intensity rating,

Health anxiety and Walk performance
Decision to perform 1 study of expert Uncertain indicators: pain and functional limitations
367
arthroplasty opinions (N=125 described as ‘moderate’
orthopaedic surgeons) Significant indicators: Pain and functional limitation
Panel scoring of appropriateness was more related to
level of pain and to functional limitation than the other
variables (age, surgical risk, previous nonsurgical
treatment) for the decision to perform arthroplasty
Indications for 1 study of expert Indications:
276
surgery opinions (N=378 At least have severe daily pain rest pain and transfer pain
orthopaedic surgeons) (eg. Standing up from a sitting position) several days/week
Unable to walk more than 3 blocks or up to 10 blocks
413
Osteoarthritis
Symptoms, Function
and QoL outcome Reference Outcome / Effect size
Difficulty climbing stairs and any difficulty putting on
shoes and socks
Reduced ROM of the hip need not be marked - flexion >
45o
Unable to walk up to 10 blocks
Indications for 1 study of expert Rest pain and pain with activity = highly important
128
surgery opinions (N=304 indicators for
orthopaedic surgeons, Range of motion = much less important indicator
N=314 referring Pain severity = important: severe pain, rest pain or night
physicians) pain and need for analgesics should be present on several
days/week before THR is considered
Functional items such as difficulty climbing stairs and
putting on shoes and socks: more referring physicians
than surgeons indicated that these were very important
criteria
Heterogeneity within each group on appropriate levels of
pain and functional impairment
Reduced walking distance = important indicator (degree of
restriction ranged from <1 km and <0.5 km)
Other impairments (including climbing stairs, putting on
shoes and socks and the need for a crutch): referring
physicians required more advanced disease as
prerequisite than surgeons.
QoL issues, ADLs, sports and sex = most important
additional items
Overall ranking of importance for pain symptoms: rest
pain, night pain and pain with activities.
Appropriateness of 1 study of expert Presence or absence of disability = not influential factor
213
surgery opinions (N=8
orthopaedic surgeons,
N=8 GPs)
Hip or knee
Definite willingness 1 observational- Willingness not associated with WOMAC disease severity
to undergo correlation score
179
arthroplasty study (N=1027)
Osteoarthritis Grade
Two studies 227 91 looked at osteoarthritis grade as indications for surgery in knee osteoarthritis
patients. Both studies found that patients with more severe disease were more willing to undergo
surgery and were more likely to be referred for surgery.
Two studies 329 213 looked at osteoarthritis grade as indications for surgery in hip osteoarthritis
patients. Both studies found that more severe disease was a more important indicator for surgery.
Table 275: Effect of grade of OA on attitudes towards surgery for OA

osteoarthritis grade
Knee osteoarthritis
Patient’s willingness 1 cross-sectional OR per 10-point increase of NZ score 1.57, 95% CI 1.47
414
Osteoarthritis
osteoarthritis grade
227
to undergo surgery study (N=26,046) to 1.66
Favours more severe disease (more willing)
Referral for surgery 1 study of expert Moderate-severe knee osteoarthritis by radiography =

91
opinions ( N=244 Family more likely to refer
Physicians and N=96
Rheumatologists)
Hip
Indications for 1 study of expert Functional Class I: pain is mild or osteotomy an option =
329
surgery opinions (N=11 experts) inappropriate. Moderate pain osteotomy no option =
case-specific judgement
Functional Class III: patients < 60 years old = osteotomy
preferable and mild pain = cautious for surgery unless
good chance of prosthesis survival Patients > 60 years
old = moderate and severe pain + impaired ADLs are
strong indicators.
Functional class IV: Patients usually bedbound /
wheelchair so pain on activity not a factor. Severe rest
pain = potentially appropriate regardless of other
factors, as surgery may be only way to relieve pain.
Some expectation of improvement in function =
surgery appropriate. Mild to moderate pain + little
expectation of functional improvement = need careful
weighing of risks and benefits.
Urgency for surgery 1 study of expert Functional Class I: mild pain on activity and no rest pain
329
opinions (N=11 experts) = low priority; moderate pain during activity = higher
priority; rest pain and/or work or caregiving impeded =
high priority
Functional Class III: severe pain on activity (unless rest
pain absent or mild) = Higher priority. Severe pain on
activity and at rest = surgery must be provided as soon
as possible
Functional class IV: most patients have severe and
longstanding arthritis affecting most joints thus surgery
= limited benefits for function. Moderate to severe rest
pain = surgery should be provided quickly. High priority
= those few patients with moderate rest pain who may
only recently have become confined to a wheelchair or
bed and have good prospects of walking again. Delay
may reduce their chances of rehabilitation.
Indications for 1 study of expert opinions Severity of hip = most important indicator
213
surgery (N=8 orthopaedic least severe grades (Charnley class 4 and 5) =
surgeons, N=8 GPs) inappropriate
Charnley grades 1 or 2 = appropriate for those with low
comorbidity or medium comorbidity if not severely
overweight
Willingness
One study227 looked at willingness of knee osteoarthritis patients to undergo surgery and found that
approximately one third of patients would not accept surgery if offered and they were concerned wit
the risks and benefits of surgery.
415
Osteoarthritis
One study179 looked at willingness of hip or knee osteoarthritis patients in high and low-rate surgery
areas to undergo surgery and found that patients in high rate arthroplasty areas were more willing to
undergo surgery.
Table 276: Willingness to undergo surgery for OA

Willingness outcome Reference Outcome / Effect size
Knee osteoarthritis
Patient’s willingness 1 cross-sectional Approximately one third of participants considered for
227
to undergo surgery study (N=26,046) TKR indicated that they would not accept surgery if
offered.
Majority concerned about risks and benefits of TKR.
Hip or knee
Willingness to 1 observational- FOR PATIENTS WITH SEVERE ARTHRITIS:
undergo arthroplasty correlation Definitely willing: 8.5% and 14.9% (in low-rate and high-
179
study (N=1027) rate arthroplasty areas)
Probably willing: 17.5% and 21.5% (in low-rate and
high-rate arthroplasty areas)
Unsure: 18.5% and 19.4% (in low-rate and high-rate
arthroplasty areas)
Definitely or probably unwilling: 55.5% and 44.2% (in
low-rate and high-rate arthroplasty areas)
Needs for arthroplasty, adjusted for willingness
(expressed per 1000 phase I respondents): 2.4% and
5.4% (in low-rate and high-rate arthroplasty areas);
Patients in the high-rate area were significantly more
likely to know someone who had undergone joint
arthroplasty, compared to those in the low-rate area
(94.3% and 72.7% respectively, p<0.001)
Use of assistive devices
One study276 looked at the effect of usage of assistive devices by knee osteoarthritis patients on the
decision to undergo surgery and found that assistived device use did not affect the decision to
perform surgery.
One study276 looked at the effect of usage of assistive devices by hip osteoarthritis patients on the
decision to undergo surgery and found that overall, assistive device use did not affect the decision to
perform surgery.
Table 277: Effect of assistive devices on attitude towards surgery for OA

Assistive devices
Knee osteoarthritis
Indication for 1 study of expert Assistive device was not a uniform requirement - use of
276
surgery opinions (N=378 a cane or crutch several days/week or less often to be
orthopaedic surgeons) consistent with TKA
Hip
Indication for 1 study of expert Assistive device was not a uniform requirement - use of
276
surgery opinions (N=378 a cane or crutch several days/week or less often to be
orthopaedic surgeons) consistent with TKA
More Canadian than US surgeons required an assistive
device to be used every day and the use of a cane with
416
Osteoarthritis
Assistive devices
stairs
Patient psychological factors (including expectations)
Three studies1,91,276(N=13 experts) looked at the effect of psychological factors on indications for
surgery in knee osteoarthritis patients and all studies found that psychological factors were
important indicators affecting the decision to perform surgery.
One study276 looked at the effect of psychological factors on indications for surgery in hip
osteoarthritis patients and all studies found that psychological factors were important indicators
affecting the decision to perform surgery.
Table 278: Effect of psychological factors in attitudes towards surgery for OA

Patient
psychological
factors outcome Reference Outcome / Effect size
Knee osteoarthritis
Indication for 1 study of expert desire to derive psychological benefit from surgery,
276
surgery opinions (N=378 desire to return to sports, unrealistic expectations,
orthopaedic surgeons) poor motivation, limited cooperation, hostile
personality, depression and dementia = sway decision
against surgery
Wanting to be independent and return to work = sway
decision for surgery and was the most favourable
factor
US surgeons had a greater tendency to rate borderline
mental status and other psychiatric diagnoses more
unfavourably than Canadian surgeons
Referral for surgery 1 study of expert Patient demands KR and Sensation of instability by
91
opinions ( N=244 Family patient = more likely to refer
Physicians and N=96 Major psychiatric disorders = less likely to refer
Rheumatologists)
Indications for 1 study of expert The patient’s goals and expectations should be
1
surgery opinions (N=13 experts) ascertained prior to THR to determine whether they
are realistic and attainable by the recommended
therapeutic approach. Any discrepancies between the
patient’s expectations and the likely outcome should
be discussed in detail with the patient and family
members before surgery.
Hip
Indications for 1 study of expert Desire to derive psychological benefit from surgery,
276
surgery opinions (N=378 desire to return to sports, unrealistic expectations,
orthopaedic surgeons) poor motivation, limited cooperation, hostile
personality, depression and dementia = sway decision
against surgery
Wanting to be independent and return to work = sway
decision for surgery
417
Osteoarthritis
Post-operative care and Physician advice
One study276 looked at the effect of home care on the decision to perform surgery in knee
osteoarthritis patients and found that limited home care did not affect the decision to perform
surgery.
Two studies276,367 looked at the effect of limited home care and previous nonsurgical treatment and
surgical risk on indications for surgery in hip osteoarthritis patients and found that limited home care
did not affect the decision to perform surgery but previous nonsurgical treatment and surgical risk
significantly affected the decision.
One study179 looked at the effect of interaction with their physician on willingness to undergo surgery
in patients with hip or knee osteoarthritis and found mixed results.
Table 279: Effect of postoperative care and physician advice on attitudes to surgery for OA
Post-operative care
and Physician advice
Knee osteoarthritis
Indication for surgery 1 study of expert Limited home care = no effect on decision for
276
opinions (N=378 surgery
orthopaedic surgeons) Limited home care and inadequate available
rehabilitation = mostly rated neutral
Hip
Decision to perform 1 study of expert Surgical risk and previous nonsurgical treatment =
367
arthroplasty opinions (N=125 significantly associated with decision
orthopaedic surgeons)
276
Indications for 1 study of expert opinions Limited home care = no effect on decision for
surgery (N=378 orthopaedic surgery
surgeons)
Hip or knee
Definite willingness 1 observational-correlation There was NS difference between patients suitable
179
to undergo study (N=1027) for arthroplasty in the low-and high-rate
arthroplasty arthroplasty areas for: number of patients under
the care of a physician for their arthritis and
number of patients having discussed arthroplasty
with their physician
Patients suitable for arthroplasty in the low-rate
arthroplasty area had a significantly higher number
of patients who were recommended by their
physician for arthroplasty (20% and 28% of
potential candidates respectively, p<0.001).
Definite willingness to undergo arthroplasty was
significantly associated with having ever spoken
with a physician (OR 2.93, p=0.0001)
418
Osteoarthritis
11.1.5 Evidence statements: predictors of benefit and harm
11.1.5.1 Age
Knee osteoarthritis
Peri-operative complications / hospital stay
One case-series222 (N=454) found that for TKA patients:

 There was NS difference between younger and older patients for length of stay in the acute care
setting or rehabilitation facilities and in-hospital complications;
 Older age group were more likely to be transferred to rehabilitation facilities regardless of joint
type replaced (Older patients with TKA = 83%, younger patients 40%).
One case-series423 (N=124) found that:

 Older age (71-80 years or ≥81 years versus 65-70 years) was a significant predictor of AEs;
 Patients at low risk of AEs included those with fewer than 2 of the following risk factors: age >70
years, male gender, 1 or more comorbid illnesses:
 Age 71-80 years: OR 1.3 (95% CI 1.0 to 1.6);
 Age 81-95 years: OR 1.6 (95% CI 1.1 to 2.4).
One case-series164 (N=3048) found that older patients had a much higher mortality rate post TKR:
 Patients aged <65 years: mortality rate 0.13% (N=1 out of N=755 patients)
 Patients aged ≥85 years: mortality rate 4.65% (N=4 out of N=86 patients)
 Risk ratio was 14 times higher in patients aged ≥85 years than the rest of the patients (OR 13.7,
95% CI 3.0 to 44.8).
Long-term survival of prosthesis
One case-series177 (N=35, 857) found that for TKA:

 Cumulative revision rate for TKA due to:
o any cause was higher in younger patients (<60 years old) than the older group (≥60 years old)
at 8.5 years post-surgery (13% and 6% respectively);
o loosening of components was higher in younger patients (<60 years old) than the older group
(≥60 years old) at 8.5 years post-surgery (6% and 2.5% respectively).
 While for TKA patients regression analysis showed that risk for revision due to:
o any cause was significantly lower (risk ratio 0.49, 95% CI 0.38 to 0.62, p=0.0000) in the older
patients (≥60 years) compared to younger patients (<60 years);
o loosening of components was significantly lower (risk ratio 0.41, 95% CI 0.27 to 0.62,
p=0.0000) in the older patients (≥60 years) compared to younger patients (<60 years);
o any cause attributable to year of surgery decreased each year (risk ratio 0.92, 95% CI 0.89 to
0.96, p=0.0000) in the older patients (≥60 years) compared to younger patients (<60 years);
o loosening of components attributable to year of surgery decreased each year (risk ratio 0.87,
95% CI 0.82 to 0.94, p=0.0001) in the older patients (≥60 years) compared to younger patients
(<60 years);
o infection attributable to year of surgery decreased each year (risk ratio 0.91, 95% CI 0.85 to
0.96, p=0.0015) in the older patients (≥60 years) compared to younger patients (<60 years)
419
Osteoarthritis
o And that there was no significant difference between the older (≥60 years) and younger
patients (<60 years), for risk of revision due to infection.
The same case-series177 (N=35, 857) found that for unicompartmental KA cumulative revision rate
due to:
 any cause was higher in younger patients (<60 years old) than the older group (≥60 years old) at
9.2 years post-surgery (22% and 14% respectively);
 loosening of components was higher in younger patients (<60 years old) than the older group
(≥60 years old) at 9.5 years post-surgery (8% and 6.5% respectively).
 Whilst regression analysis showed that for unicompartmental KA patients:
o risk for revision due to any cause was significantly lower (Risk ratio 0.55, 95% CI 0.45 to 0.65,
p=0.0000) in the older patients (≥60 years) compared to younger patients (<60 years);
o risk for revision due to loosening of components was significantly lower (Risk ratio 0.63, 95% CI
0.48 to 0.83, p=0.0012) in the older patients (≥60 years) compared to younger patients (<60
years);
o there was no significant difference between the older (≥60 years) and younger patients (<60
years), for risk of revision due to infection;
o risk for revision (due to any cause) attributable to year of surgery decreased each year (Risk
ratio 0.94, 95% CI 0.91 to 0.97, p=0.0001) in the older patients (≥60 years) compared to
younger patients (<60 years);
o risk for revision (due to loosening of components) attributable to year of surgery decreased
each year (Risk ratio 0.91, 95% CI 0.87 to 0.96, p=0.0002) in the older patients (≥60 years)
compared to younger patients (<60 years);
o there was no significant difference between the older (≥60 years) and younger patients (<60
years), for risk of revision due to infection attributable to year of surgery.
Symptoms (Pain, stiffness), Function, QoL

 Younger age was a predictor of poor outcome (high pain score);
 Age was a significant predictor of TKR outcome:
 Younger patients were significantly associated with poor outcome (high pain score), pain at 5
years post-surgery (17% aged <60 years vs 7% aged 60-64, p<0.05; 13% aged 60-70; 7% aged >70);
 Patients aged <60 years are more than twice as likely to report poor outcome scores (high pain at
5 years post-surgery) than those >60 years;
 Patients who had unilateral TKA (first knee) and those who had staged unilateral TKA (second
knee) were significantly more likely to have poor outcome scores (high pain at 5 years post-
surgery) than those who had bilateral TKA at the same time (13%, 6% and 2% respectively,
p<0.01);
One case-series222 (N=454) found that for TKA patients, age was not a strong predictor of post-
operative WOMAC pain or function.
One case-series266 (N=860) found that older age was a strong predictor of SF-36 physical functioning
at 2 years post-surgery.
One case-series137(N=855) found that age was:

 associated with post-operative SF-36 scores and WOMAC scores.
 not a predictor of post-operative SF-36 physical function, bodily pain, vitality, social functioning,
role emotional, mental health, role physical
420
Osteoarthritis
 a predictors of post-operative SF-36 general health

 a predictor of post-operative WOMAC pain, and stiffness
 not a predictor of post-operative WOMAC function
Hip osteoarthritis
One case-series222 (N=454) found that for THA patients there was a NS difference between younger
and older patients for:
 length of stay in the i) acute care setting; ii) rehabilitation facilities
 in-hospital complications
Whilst the older age group were more likely to be transferred to rehabilitation facilities regardless of
joint type replaced.
One case-series221 (N=36, 984) found that:

 Older age was associated with increased RR of failure: In patients aged ≥80 years (RR 1.6, 95% CI
1.0 to 2.6) compared with patients aged 60-69 years at 0-30 days after primary THR.
 Younger age was associated with increased RR of failure: In patients aged 10 to 49 years (RR 1.7,
95% CI 1.3 to 2.3) and patients aged 50 to 59 years (RR 1.3, 95% CI 1.0 to 1.6) compared with
patients aged 60-69 years. Patients aged 70-79 years and ≥80 years were associated with a lower
RR for failure (RR 0.9, 95% CI 0.7 to 1.0) and (RR 0.6, 95% CI 0.5 to 0.8) respectively at 6 months to
8.6 years after primary THR.

 One case-series222 (N=454) found that for THA patients, age was not a strong predictor of post
operative WOMAC pain or function
One case-series386 (N=12,925) found by linear regression that patients were an average of 1.6 years
older per category of reduced pre-operative walking capacity (p<0.01; effect size 0.4), indicating that
age had a moderate effect on deterioration of pre-operative walking capacity.
Thumb osteoarthritis
Symptoms (pain, stiffness), function, QoL
One case-series107 (N=36) found that age at operation was not a significant predictor of surgical
outcome (DASH score - Disabilities of the arm, shoulder and hand).
11.1.5.2 Gender
Knee osteoarthritis

 Male gender was a significant predictor of AEs;
Patients at low risk of AEs included those with fewer than 2 of the following risk factors ; age >70
years, male gender, 1 or more comorbid illnesses.
421
Osteoarthritis
One case-series177 (N=35, 857) found that for TKA there was no significant risk of TKA revision due to
any cause or component loosening associated with gender.
 Men were significantly more likely than women to have TKA revision due to infection (risk ratio
1.64, 95% CI 1.23 to 2.18, p=0.0007).
 The same case-series177 (N=35, 857) found that for unicompartmental KA there was no significant
risk of revision due to any cause or component loosening associated with gender.
 Men were significantly more likely than women to have unicompartmental KA revision due to
infection (risk ratio 1.88, 95% CI 1.13 to 3.14, p=0.0156).
One case-series135 (N=512) found that gender was not associated with outcome of TKR (pain at 5
years post-surgery).
One case-series137(N=855) found that gender was:

 Associated with post-operative SF-36 scores and WOMAC scores.
 A predictor of post operative WOMAC stiffness
 Not a predictor of post-operative:
o SF-36 physical function, bodily pain, role physical, vitality, role emotional, mental health
o WOMAC pain.
 Whilst male gender was:
o Not a predictor of post-operative SF-36 general health;
o A predictor of post-operative SF-36 social functioning and WOMAC function;
 And female gender was:
o Not a predictor of post-operative SF-36 social functioning;
o A predictor of post-operative SF-36 general health.,
Hip osteoarthritis
Long-term survival of prosthesis / hospital stay

 Male gender was associated with an increased RR of THR failure of any cause (RR 1.5, 95% CI 1.1
to 2.0) at 0-30 days (RR 1.2, 95% CI 1.0 to 1.4) at 6 months to 8.6 years after primary THR
 There was no association between THR failure and gender or age at 31 days to 6 months after
primary THR.
One cohort study333 (N=3144) found that:

 There was no difference between men and women for post-operative outcome (WOMAC and SF-
36) at 6 months and 12 months post-THR surgery.
 Gender was not associated with post-operative WOMAC pain or physical function at 12 months
post-THR surgery.
422
Osteoarthritis
One case-series61(N=71) found that women had a higher prosthesis survival rate than men (N=7, 85%
and N=4, 36% respectively).
11.1.5.3 Weight/BMI
Knee osteoarthritis
One case-series303 (N=124) found that body weight ≥180 lbs was not significantly associated with
symptomatic pulmonary embolism.
One case-control study9(N=79) found that overall rate of complications following TKR was
significantly higher in the morbidly obese group compared to the non-obese group (32% and 0%
respectively, p=0.001).
One case-control study426 (N=656) found that:

 There was NS difference between obese and non-obese patients for percentage of revisions (4.9%
and 3.1% respectively);
 Revision due to osteolysis was significantly higher in the obese group compared to the non-obese
group (p=0.016);
 Higher BMI was associated with an increase in incidence of focal osteolysis;
 Survival analysis showed NS difference for revision of any component between obese and non-
obese patients (98.1% and 99.9% survival rates respectively). This similarity was maintained until
the 10th year post-operatively (97.2% and 95.5% respectively).
One case-control study9(N=79) found that overall rate of TKR revisions and revisions plus pain (5-year
survivorship) was significantly higher in the morbidly obese group compared to the non-obese group
(p=0.01 and p=0.02 respectively)

 One case-series104 (N=101) found that improvement in post-operative QoL was significantly
greater in the obese groups compared to the non-obese group.
 Two case-control studies 426 9 found that there was NS difference between obese and non-obese
patients for KSS score at the most recent follow-up for function, absolute improvement and knee
scores,
One case-series137(N=855) found that BMI was not associated with post-operative SF-36 scores and
WOMAC scores.
Hip osteoarthritis

 Increasing BMI was significantly associated with length of stay in hospital (p<0.001)
423
Osteoarthritis
 Compare with the normal weight group, mean length of hospital stay increased 4.7% in the
overweight group and 7.0% in the obese group (multivariate logistic regression)
 There was NS association between increasing BMI and risk of systemic post-operative
complications
 In the obese group, there was a 58% risk (OR 1.58, 95% CI 1.06 to 2.35) of systemic post-operative
complications compared to those of normal weight.

 There was no correlation between pre-operative BMI and post-operative mobility, WOMAC pain,
function or other complications;
11.1.5.4 Smoking
Hip osteoarthritis

 There was NS association between smoking status or tobacco preference and the mean length of
stay (after adjusting for covariates of age, BMI and so on).
 Smoking status was significantly increased the risk of systemic post-operative complications
(p=0.013);
 Previous and current smokers had increased risks of suffering from post-operative complications
compared with non-smokers (multivariate logistic regression analysis): 43% (OR 1.32, 95% CI 1.04
to 1.97) and 56% (OR 1.56, 95% CI 1.14 to 2.14) respectively
 There was NS association between post-operative complications and preference for different
tobacco products
 Number of pack years of tobacco smoking was significantly associated with increased risk of
systemic post-operative complications (p=0.004)
 The heaviest tobacco smoking group was associated with a 121% (OR 2.21, 95% CI 1.28 to 3.82)
increased risk of systemic complications compared to non-smokers (multivariate logistic
regression analysis)
 There was NS difference between smoking for:
o 0-19.9 pack years and non-smokers for risk of systemic complications
o Status, preference of tobacco product or pack years and local complications.
11.1.5.5 Co-morbidities
Knee
One case-series164 (N=3048) found that cardiovascular comorbidities significantly influenced

mortality rate after TKR (p<0.0001). Risk of mortality associated with comorbidities was 16 times
higher than when comorbidities were absent (OR 15.9, 95% CI 3.4 to 143.5).
424
Osteoarthritis
One case-series266 (N=860) found that a greater number of co-morbid conditions was a strong
predictor of SF-36 physical functioning at 2 years post-surgery.
One case-series137(N=855) found that:

 Low back pain and comorbidities were associated with post-operative SF-36 scores and WOMAC
scores.
 Low back pain and Charlson Index were not predictors of post-operative SF-36 physical function;
 Low back pain and Charlson Index were predictors of post-operative SF-36 bodily pain;
 Charlson index 1 and low back pain were not predictors of post-operative SF-36 general health;
 Charlson Index ≥2 was a predictor of post-operative SF-36 general health;
 Low back pain and Charlson Index were not predictors of post-operative SF-36 role physical;
 Low back pain and Charlson Index were predictors of post-operative SF-36 vitality;
 Low back pain was not a predictor of post-operative SF-36 social functioning;
 Charlson index was a predictor of post-operative SF-36 social functioning;
 Low back pain and Charlson Index ≥2 were not predictors of post-operative SF-36 role emotional;
 Charlson Index 1 was a predictor of post-operative SF-36 role emotional;
 Gender, age and Charlson Index were not predictors of post-operative SF-36 mental health;
 Low back pain was a predictor of post-operative SF-36 mental health;
 Charlson Index 1 was not a predictor of post-operative WOMAC Pain;
 Low back pain and Charlson Index ≥2 were predictors of post-operative WOMAC pain;
 Charlson Index 1 was not a predictor of post-operative WOMAC Function;
 Low back pain and Charlson Index ≥2 were predictors of post-operative WOMAC function;
 Charlson Index was not a predictor of post-operative WOMAC stiffness;
 Low back pain and Charlson Index were predictors of post-operative WOMAC stiffness.
Hip osteoarthritis

 Comorbid illnesses (1 or 2+ versus none) was a significant predictor of AEs.
 Patients at low risk of AEs included those with fewer than 2 of the following risk factors: age >70
years, male gender, 1 or more comorbid illnesses.

 A high co-morbidity index score was a strong predictor of THR failure compared with a low co-
morbidity index score (RR 2.3, 95% CI 1.6 to 3.5) at 0-30 days and (RR 3.0, 95% CI 2.1 to 4.5) at 31
days to 6 months after primary THR.
 A medium co-morbidity index score was associated with reduced RR of failure (RR 0.7, 95% CI 0.6
to 0.8) compared to a low co-morbidity score whereas a high co-morbidity index score was a
strong predictor of THR failure compared with a low co-morbidity index score (RR 2.8, 95% CI 2.3
to 3.3) at 6 months to 8.6 years after primary THR.
425
Osteoarthritis
One case-series386 (N=12,925) found that co-morbidities influenced the post-operative walking
capacity: there was a consistent increase in the percentage of Charnley class-C patients with each
decrease in category of pre-operative walking capacity at each of the follow-up years.
11.1.5.6 Structural features
Knee osteoarthritis
One cohort study58 (N=146) found that in TKA patients pre-operative Charnley or modified Charnley
Class C was not a predictor of post-operative WOMAC function.
One case-series168 (N=68) found that preoperative medial femorotibial narrowing did not influence
post-operative (valgus tibial osteotomy) functional outcome at the time of last follow-up or
radiographic outcome at 1 year post-surgery;
Hip osteoarthritis
One cohort study58 (N=146) found that in THA patients, pre-operative Charnley or modified Charnley
Class C was not a predictor of post-operative WOMAC function.

 Patients with a greater degree of pre-surgery cartilage space loss had significantly less hip pain at
6 months (p=0.0016) and 1 year (p=0.0028) post-THR surgery;
 There was NS association between degree of cartilage space loss and hip pain at 3, 5 and 7 years
post-THR surgery;
 Patients with pre-surgery superior cartilage space loss (femoral head migration) had significantly
less pain at 6 months post-THR surgery (p<0.05) compared to those with mainly global or medial
hip cartilage space;
 There was NS association between pre-surgery osteophyte formation and post-THR pain;
 There was NS association between the pre-surgery degree of cartilage space loss, direction of
cartilage space loss or osteophyte formation and post-operative Harris Hip Score at 1 month, 3
months, 5 years and 7 years post-THR surgery.
Shoulder osteoarthritis

 Patients with rotator cuff tear that were treated with total shoulder arthroplasty had better
postoperative active external rotation that those treated with hemiarthroplasty;
 Preoperative glenoid erosion significantly affected postoperative ROM for patients with
hemiarthroplasty
 Patients with moderate-severe glenoid erosion treated with total arthroplasty had significantly
greater increase in postoperative active external rotation compared to hemiarthroplasty
(p=0.0013);
426
Osteoarthritis
 There was NS difference between total and hemiarthroplasty patients with glenoid erosion for
postoperative active forward flexion;
 There was NS difference between total and hemiarthroplasty patients with or without glenoid
erosion for postoperative American Shoulder and Elbow Surgeons scores;
 Degree of glenoid erosion did not affect the outcome of shoulder arthroplasty in any of the
patients;
 For patients treated with total or hemi-arthroplasty, there was NS difference between Shoulders
with or without preoperative posterior subluxation of the humeral head for:
 Post-operative American Shoulder and Elbow Surgeons scores;
 Post-operative pain;
 Post-operative active external rotation;
 There was NS difference between total or hemi-arthroplasty patients who were without pre-
operative glenoid erosion or humeral head subluxation, for postoperative American Shoulder and
Elbow Surgeons scores.
One case-series107 (N=36) found that pre-operative web angle, hyperextension of the MCP and
flexion of the MCP were all significant predictors (p<0.05) of surgical outcome (DASH score -
Disabilities of the arm, shoulder and hand).
11.1.5.7 Symptoms, Function, QoL
Knee osteoarthritis
One case-series135 (N=512) found that pre-operative pain scores as well as mobility on stairs was a
predictors of poor outcome (high pain score).
One cohort study58 (N=146) found that in TKA patients. pre-operative WOMAC function was:
 significantly associated with post-operative function (p<0.001);
 a significant predictor of higher post-operative WOMAC function (OR 1.15, 95% CI 1.04 to 1.28).

 Pre-operative WOMAC pain score was a strong determinant of post-operative WOMAC pain at 1
and 2 years post-surgery;
 Pre-operative SF-36 score was a strong determinant of post-operative WOMAC pain at 1 and 2
years post-surgery;
 Pre-operative WOMAC function score was a strong determinant of post-operative WOMAC
function at 1 and 2 years post-surgery;
 There was NS difference between men and women with respect to WOMAC function at 1 year
and 2 years post-surgery;
 Patients with pre-operative WOMAC function in the lowest quartile (<34) had considerable
functional disability after TKA (mean scores 62.1 and 59.8 for 1 year and 2 years post-surgery);
 Patients with pre-operative WOMAC function in the lowest quartile (<34) had considerable
functional disability after TKA (mean scores 62.1 and 59.8 for 1 year and 2 years post-surgery);
427
Osteoarthritis
 Patients with pre-operative WOMAC function in the lowest quartile (<34) had the greatest
improvement in WOMAC function after TKA compared to other groups: they were over 4 times
more likely (OR 4.12, 95% CI 2.86 to 6.25) to have a score of ≤60 at 2 years post-surgery than
patients with pre-oeprative WOMAC function score of >35.
 Pre-operative SF-36 physical functioning score was a strong predictor of SF-36 physical
functioning at 1 year and 2 years post-surgery
 Older age and greater number of co-morbid conditions were also strong predictors of SF-36
physical functioning at 2 years post-surgery.
One case-series237(N=812) found that:
 There was NS difference between men and women for post-operative improvement in AKS score
at 5 years post-TKR
 Increased age (up to 70-73 age-group) was associated with an increase in post-operative
improvement in AKS score at 5 years post-TKR
 Older age (>73 years) was associated with a significant decrease (p<0.05) in post-operative
improvement in AKS score at 5 years post-TKR – the 79-86 year age-group showed the least
improvement
 Patients with the worst pre-operative AKS scores had significantly greater improvement (p<0.001)
in AKS score at 5 years post-TKR compared to those with higher pre-operative AKS scores
One case-series137(N=855) found that pre-operative SF-36 domains for mental health and:
 physical function were predictors of post-operative SF-36 physical function;
 bodily pain were predictors of post-operative SF-36 bodily pain;
 general health were predictors of post-operative SF-36 general health;
 role physical were predictors of post-operative SF-36 role physical;
 vitality were predictors of post-operative SF-36 vitality;
 social functioning were predictors of post-operative SF-36 social functioning;
 role emotional were predictors of post-operative SF-36 role emotional;
 pre-operative WOMAC pain were predictors of post-operative WOMAC pain;
 pre-operative WOMAC function were predictors of post-operative WOMAC function;
 pre-operative WOMAC stiffness were predictors of post-operative WOMAC stiffness.
Hip osteoarthritis
One cohort study58 (N=146) found that in THA patients, pre-operative WOMAC function was:
 significantly associated with post-operative function (p<0.005)
 a significant predictor of higher post-operative WOMAC function (OR 1.44, 95% CI 1.07 to 1.92).
One cohort study333 (N=3144) found that pre-operative:

 pain was significantly associated with post-operative pain at 12 months (p=0.011);
 physical function was significantly associated with post-operative physical function at 12 months
(p<0.006).
One case-series386 (N=12,925) found that:

 There was NS difference between the proportion of pain-free patients in any of the pre-operative
pain categories
428
Osteoarthritis
 There were significant differences (p<0.01) between the pre-operative walking capacity groups
with respect to post-operative walking capacity >60 minutes.
 Patients with the worst pre-operative walking capacity had the worst post-operative recovery of
walking capacity
 Patients with the highest pre-operative walking capacity had the best post-operative walking
capacity
 There were significant differences (p<0.01) between the pre-operative hip flexion groups with
respect to post-operative hip flexion.
 Patients with pre-operative flexion ≤70o had the worst post-operative recovery of motion
(flexion)
 Patients with excellent range of pre-operative flexion sustained a slight loss of flexion range post-
surgery.
 Patients with excellent pre-operative hip ROM (flexion) were an average of 3 years older (p<0.01)
than those with the poorest pre-operative ROM.
Shoulder

 Severity of preoperative loss of passive external rotation was found to significantly affect the
postoperative range of external motion (p=0.006):
 Hemiarthroplasty: patients with preoperative external rotation of <10o had mean postoperative
external rotation of 25o , compared to those with pre-operative ≥10o had mean 47o
postoperatively;
 Total arthroplasty: patients with preoperative external rotation of <10o had mean postoperative
external rotation of 43o, compared to those with pre-operative ≥10o had mean 50o
postoperatively.
 Preoperative internal rotation contracture did not have an adverse effect on results of total
shoulder arthroplasties;
 The severity of preoperative loss of forward flexion had no effect on postoperative forward
flexion after either hemi- or total- arthroplasty;
 Presence of full thickness repairable rotator cuff tear (isolated to the supraspinatus tendon) did
not affect post-operative American Shoulder and Elbow Surgeons scores for pain or function,
decrease in pain or patient satisfaction.
One case-series107 (N=36) found that range of motion was not a significant predictors of surgical
429
Osteoarthritis
11.1.5.8 Osteoarthritis Grade
Hip osteoarthritis
One cohort study333 (N=3144) found that:

 Patients with severe pre-operative radiographic osteoarthritis did not differ from the moderate
osteoarthritis group with respect to post-operative SF-36 and WOMAC scores at 6 months and 12
months post-THR surgery;
 Pre-operative radiographic grade of osteoarthritis was not associated with post-operative
WOMAC Pain or physical function at 12 months post-THR surgery.

 Pre-operative Hip Grade was not associated with post-operative Harris Hip score;
 Post-operative UCLA activity scores were similar for all Pre-operative Hip Grades;
 Pre-operative Hip Grade influenced the amount of post-operative pain:
 Mild-moderate pain was significantly less frequent at latest follow-up in Grade A hips compared
to Grade B and C combined (3% and 18% respectively, p=0.03);
 Pre-operative lower grade hips showed greater post-operative improvement in ROM:
 Improvement in flexion, extension, abduction and external rotation were significantly greater in
Grade B and C hips combined compared to Grade A (all: p<0.04).
One case-series107 (N=36) found that radiographic stage was not a significant predictor of surgical
11.1.5.9 Other outcomes
Knee osteoarthritis
One case-series137(N=855) found that social support was:

 associated with post-operative SF-36 scores and WOMAC scores.
 not a predictor of post-operative SF-36 physical function, bodily pain, vitality, social functioning,
WOMAC stiffness
 a predictor of post-operative SF-36 general health, role physical, role emotional, mental health,
WOMAC pain, WOMAC function,
 hospital was not associated with post-operative SF-36 scores and WOMAC scores.

 Pre-operative Hb level ≥14 g/L was significantly associated with the development of symptomatic
pulmonary embolism (p=0.011);
430
Osteoarthritis
 Bilateral TKA was significantly associated with the development of symptomatic pulmonary
embolism (p≤0.05).
 Pre-operative Hb level ≥14 g/L was a predictor of pulmonary embolism (OR 2.4, 95% CI 1.2 to 4.6);
 Bilateral TKA was a predictor of pulmonary embolism (OR 7.2, 95% CI 1.3 to 39.6).
One case-series107 (N=36) found that surgical procedure and hand dominance were not significant
predictors of surgical outcome (DASH score - Disabilities of the arm, shoulder and hand).

We looked at studies that conducted economic evaluations involving referral to joint surgery for
patients with osteoarthritis. One paper from New Zealand investigating 153 patients on orthopaedic
waiting lists was found.144 The paper investigates the waiting times for patients, and the cost incurred
by the patients, as well as considering the health status of patients at different time points before
and after surgery. The paper found that the cost is significantly higher for patients who wait longer
than 6 months for surgery compared to patients who wait less than 6 months. However it is
interesting to note that this is from a societal perspective. Costs are significantly higher for personal
and societal costs for the group that waits over 6 months, but for medical costs alone the cost is
higher but not statistically significantly so. The paper also finds that the health of patients generally
worsens over time up until their operation, after which health improves, suggesting that the longer a
patient waits the more health losses they accrue as opposed to someone who is treated more
quickly.

Although demand and frequency of joint replacement continues to rise there is very little evidence
upon which to base decisions about who to refer. The most effective techniques for defining criteria
to guide appropriate referral have been the development of expert guided consensus. The purpose
of these criteria is to quantify the benefit /risk ratio in order to inform patients and referrers of the
appropriateness of treatment. However each decision remains individual and ultimately it is the
patient who must decide on their own risk / benefit calculation based upon the severity of their
symptoms, their general health, their expectations of lifestyle and activity and the effectiveness of
any non-surgical treatments. Referral for consideration of surgery should allow all patients who may
benefit to have access to a health worker, usually the surgeon, who can inform that decision.
The use of orthopaedic scores and questionnaire based assessments has become widespread. These
usually assess pain, functional impairment and sometimes radiographic damage. The commonest are
the New Zealand score and the Oxford Hip or Knee score. Many (such as the Oxford tools) were
designed to measure population based changes following surgery, and none have been validated for
the assessment of appropriateness of referral.
Similarly the use of radiographic reports as a basis for referral decisions is unreliable. This is because
radiographs appearances do not correlate well with symptoms, significant painful lesions may not be
detectable on plain radiographs and the radiographs are often inadequately performed eg. non-
weight bearing radiographs of the knee.
The restriction of referral for consideration of surgery based upon other health issues such as BMI
age or co-morbidities has no basis in evidence. There are some groups of patients for whom the risks
of post-operative complication may be slightly higher or the long term outcomes of joint
431
Osteoarthritis
replacement worse but there is no evidence supporting these as reasons to deny treatment. Indeed
there is evidence to suggest these patients can have greater benefit than other groups.
35.Clinicians with responsibility for referring a person with osteoarthritis for consideration of joint
surgery should ensure that the person has been offered at least the core (non-surgical)
treatment options (see recommendation 6 and Figure 3 in section 4.1.2). [2008]
36.Base decisions on referral thresholds on discussions between patient representatives, referring

clinicians and surgeons, rather than using scoring tools for prioritisation. [2008, amended 2014]
37.Consider referral for joint surgery for people with osteoarthritis who experience joint
symptoms (pain, stiffness and reduced function) that have a substantial impact on their quality
of life and are refractory to non-surgical treatment. [2008, amended 2014]
38.Refer for consideration of joint surgery before there is prolonged and established functional
limitation and severe pain. [2008, amended 2014]
39.Patient-specific factors (including age, sex, smoking, obesity and comorbidities) should not be
barriers to referral for joint surgery. [2008, amended 2014]
432
Osteoarthritis
Consideration of timing for surgery
12 Consideration of timing for surgery

12.1 Introduction
Surgical management strategies including total joint arthroplasty (TJA) can be highly successful
interventions in selected people with osteoarthritis. The consideration of referral to surgical
specialties and the ultimate decision to undertake surgical options is a shared decision between
health care professionals and people. CG59 made recommendations regarding referral for specialist
services. Adequate and accurate information provided at all stages throughout the patient pathway
is a crucial component to making the right decision for each individual patient at that specific time.
The two main settings in which discussions surrounding surgical options take place are general
practitioners considering referral of people to surgical specialties, and with orthopaedic surgeons in
secondary care considering if surgery is a viable option for people referred. Numerous patient
information leaflets (PILs) and internet resources are available concerning surgical management
options in osteoarthritis, this combined with expertise and knowledge of health care professionals
should be delivered well to ensure productive collaboration. The GDG wanted to identify what the
information needs were for patients who were considering what was the most appropriate time for
sugery based on their individual circumstances.
12.1.1 What information should people with OA receive to inform consideration of the
appropriate timing of referral for surgery as part of their OA management?
Update 2014

Population Adults with confirmed diagnosis of OA
Intervention/s • Information provided to inform consideration of the appropriate timing for referral
for total joint replacement (pre waiting list and pre-surgery)
• Information that people would like to have known prior to considering total joint
replacement (whilst on waiting list or post- surgery)
Comparison/s • No information
• Different types of information
Outcomes • Patient views/experiences
• Patient preference/satisfaction
• Patient knowledge
Study design Qualitative studies, surveys, cross-sectional studies

Seven qualitative studies were included in the review, 109,125,203,233,279,296,433 and these were
supplemented with data from one cross-sectional survey71, and one longitudinal study. 295
The review only considered studies which contained data regarding information provision to people
with OA along the total joint replacement pathway. See also the study selection flow chart in
Appendix D, study evidence tables in Appendix G and exclusion list in Appendix J.
Quality of the qualitative studies was assessed using a modified version of the NICE qualitative
studies appraisal framework.
433
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Issues covered by this quality assessment were:

 Rigour of the research methodology
 quality of data collection
 clear description of role of researcher
 clear description of context
 trustworthy data collection methods
 rigorous analysis methods
 richness of data
 trustworthy data analysis methods
 convincing findings
 relevance to the aims of the study.
A summary of the study quality for the qualitative studies is presented in Table 281 and Table 282.
Table 281: Summary of studies included in the review – study quality
Study Population Methods Analysis Relevance to guideline population

279
Mann 2011 Well reported Adequately Adequately GP practice in the UK: 16 people with hip
reported reported or knee OA & 12 multidisciplinary health
care professionals
Update 2014
Demierre Well reported Poorly Poorly Partially applicable. Of n=24 interviews,
109
2011 reported reported 4 planned arthoplasties due to an
‘accident’ as opposed to OA
433
Suarez 2010 Well reported Adequately Poorly Six ethnically split focus groups n=37 in
(Duplicate reported reported primary care centres affiliated to one
study of Kroll rheumatology outpatient department in
247
2007 ) Texas, USA
Dosanjh Well reported Adequately Adequately People scheduled for or having had a
125
2009 reported reported total hip arthroplasty (n=18) in southern
California
233
Karlson 1997 Well reported Well reported Adequately People with moderately severe OA of
reported the hip or knee aged 60 or over; 18
women and 12 men; Single centre in the
USA
203
Hudak 2002 Well reported Well reported Adequately 17 elderly people with severe disabling
reported arthritis unwilling to undergo TJA
McHugh Well reported Well reported Adequately 25 with OA hip having undergone THR
296
2012 reported
Table 282: Summary of mixed methods studies in the review
Study Design Population Limitations

71
Cheung 2013 Cross- 300 consecutive people with OA of the hip/knee - Non pure OA population
sectional or avascular necrosis of the hip attending the - Concerns of generalizability
survey orthopaedic clinic in the university teaching of results
hospital in Hong Kong
McHugh Longitudi 220 people aged 18 years or older with a Non generalisable to wider OA
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Study Design Population Limitations

295
2012A nal study confirmed diagnosis of OA of the hip or knee who population. One GP referral
had been referred to orthopaedic surgery for centre to one secondary care
consideration of TJA in the north west of England setting
Thematic analysis:
Themes relating to information which shaped consideration of the appropriate timing of referral for
surgery were identified from the six qualitative studies. The themes identified have been split
temporally into two main sections: a) those encountered during the path leading to the decision for
surgery and b) those concerning post-operative life. These themes are supported by data extracted
from one cross sectional survey, and one longitudinal study.
The path leading to the decision to surgery
Information delivery:
One study279 with 16 people with hip or knee OA, 5 of whom had undergone previous total joint
arthroplasty (TJA), suggested people felt they did not receive enough information, and that the
information received contained a variety of negative messages.
“Well it’s a pity they can’t tell you how it progresses and if it progresses in everybody”
Three studies433,233,279with 83 people with hip or knee OA, 5 of whom had undergone previous TJA
Update 2014
felt that different sources of information e.g. the media, physicians and family members often gave
conflicting information, and people desired information from trusted sources.
“Well, I’ve heard on television and my sister in law and a friend of mine that had both knees done.
They had a good response from it”
One study203 with 17 people with OA, 1 of whom had undergone previous TJA, suggested that the
most useful information source was from those who have had the procedure, and that there was
large amount of fear within the OA population of misinformation.
“When I go to the mall, and with the people I was discussing it with said “don’t go for the hip
replacement… its dangerous”
This was supplemented by the results of one cross-sectional survey71 which sampled 300 people with
OA of the hip or knee and showed 77% of people received information from their friends, relatives or
neighbourhood whilst only 40% received information from a doctor. 76% wanted more information
from the television and 65% preferred obtaining information from a doctor.
Information on Illness and pain consequences:
One study109 with 28 people with hip or knee OA, 8 of whom had had previous TJA, wanted
information on the potential social, functional and psychological consequences of delaying surgery.#
“I cannot do much anymore. Everything becomes a problem really. Well when I’m at home, it is OK.
This is good. But… it’s a pity to live on in one’s apartment. It’s all over.”
Two studies203 125 with 35 people with hip and knee OA scheduled to receive or having received a TJA
requested information on the amount of pain necessary for TJA candidacy.
“If I was in constant pain, I would take it”
Information regarding and ambivalence towards medication:

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Osteoarthritis
One study109 with 24 people with hip or knee OA, eight of whom had had previous TJA suggested that
medication was problem not a solution, was a daily companion, a treacherous friend and wanted
more information on the risks of medication as an alternative to surgery
“I do not know if I’ll ever be able to stop (taking) medication. I know also the drugs I take, the pain
relievers, are not without any negative consequences on my health either”
Information on surgical procedure and prosthesis:
Five studies433,109,125 203,233 commented on the type of information that people wanted to receive
about the surgical procedure and prosthesis. Specific information included the limited life expectancy
of prosthesis, health status and risk factors associations with surgery, recovery time, complications,
less invasive options, if there could be preservation of muscles and tendons, and the incisional size.
One study233 looking at gender differences found women in particular were far more concerned
about the potential risks of surgery and generally wanted more information surrounding this than
men
“I was always told “oh you’re far too young for arthroplasty””
“I probably waited longer than I should for surgery, but I was afraid of the long recovery times. My
neighbour had had his hip replaced from the back… he had a pretty big scar and never really felt
better for six months… I mean… that’s a long-time to be recovering don’t you think?”
Information regarding local services:
One UK based study279 with 16 people with OA and 12 health care practitioners suggested people
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wanted more information on their local services given the facts there is large variation in provision of
services, access to specialist advice. The study also highlighted the need for continuity and suggested
that there was currently not enough follow up.
“It depends on this GP and that. Some send you straight to a consultant, some say “oh its old age”
and leave you to it.”
Reasons for delay:
One study looking at gender differences surrounding TJA233 and sampling 30 people with OA of the
hip or knee suggested the main reasons for delay for women was waiting until they reached a
reached a certain threshold of pain or function to be ready; no men expressed this attribute. Other
notable reasons across gender were expectation that technology would improve, and fear that
surgery may be irrecoverable.
“”when it interferes with everything you want to do and if there can be relief from an operation you
are going to do it. I mean if all of a sudden you can’t go up and down steps, you can’t play the golf
game, you can’t go shopping, you just can’t function…”
Post-operative life
Information on recovery and rehabilitation:
One study109 with 16 people with OA of the knee/hip, 5 of whom had previously had a TJA suggested
they wanted information surrounding rehabilitation after surgery prior to consideration of TJA.
“I foresee something rather hard…”
One UK study296 with 25 people with OA of the hip having undergone THR suggested they wanted
information on the challenges of recovery including:
Getting clearance from consultant and health professional guidance on recovery:

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Osteoarthritis
“Initially I went over the top with, this care about ‘don’t bend down’. I couldn’t put the fire on and I
couldn’t bath myself but then I saw my specialist who said bending down doing normal things was
OK”
“My biggest thing was the internet. I would go on and look at successes…I looked a lot at different
people’s experiences. There are a few video clips of people which one was so accurate. You know sort
of. I could identify with that”
Finding information for one’s self, particularly on the internet
“I did everything to the book… and I got to week 6 and I thought what else can I do apart from just
what they told me… and I started looking on the internet… I rung up the hospital and spoke to the
physiotherapist – about wanting to go swimming and they said wait to see the consultant”
Information relating to living with a prosthesis and its acceptance:
One study109 with 16 people with OA of the knee or hip, 5 of whom had previously had a TJA
suggested they wanted information surrounding the prosthesis itself, living with a prosthesis and
how to accept living with a prosthesis.
”it is a foreign object, a strange part”
Update 2014
Additional data:
One UK based longitudinal study295 with 220 people presented data on information provision or lack
thereof at a variety of stages of the TJA pathway:
57.5% of people wanted more information about OA: People wanted more information on causes,
progression, general management, pain management, exercises, understanding medication, diet, use
of vitamins and understanding the psychological effects of OA
20.9% replied they had never been given a diagnosis of OA
58% said they had been provided with information about OA
56.7% had not been told about exercises for OA
64.8% had not been given information regarding pain management
70.8% had not been given information on understanding their medication
Of the people who had been given information, key information sources were GPs, hospital nurses
and doctors, physiotherapists and local pharmacists.
Of people receiving a TJA within the twelve month study 73.1% didn’t not require further
information. Of the 26.9% who did require further information they wanted it regarding: expectation
of recovery, what they could and could not do after the operation; effects of surgery (e.g. leg
swelling, degree of bend in joint, wound infection); exercise and the procedure and prosthesis used.
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Update 2014
No relevant economic evaluations were identified.
Economic
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40.When discussing the possibility of joint surgery, check that the person
has been offered at least the core treatments for osteoarthritis (see
recommendation 6 and Figure 3 in section 4.1.2), and give them
information about:
 the benefits and risks of surgery and the potential consequences of
not having surgery
 recovery and rehabilitation after surgery
 how having a prosthesis might affect them
Recommendations  how care pathways are organised in their local area. [new 2014]
Relative values of The GDG considered that patient views, experiences and knowledge
different obtained were the most important outcomes to inform decision-making and
outcomes the development of this recommendation.
Trade off between The GDG wished to explore the qualitative evidence surrounding the delivery
clinical benefits and content of information provided, or indeed not provided, during
and harms people’s journeys up to and beyond the decision to refer and undertake a
Update 2014
total joint arthroplasty.
Relevant themes were extracted and grouped together temporally. The eight
thematic areas were split into two groups:
 Those encountered during the path leading to the decision for surgery:
o information delivery.
o information on illness consequences and pain;
o information regarding, and ambivalence towards, medication
o iInformation on surgical procedure and prosthesis
o information regarding local services
o reasons for delay
 Those concerning post-operative life
o information on recovery and rehabilitation
o information relating to living with a prosthesis and its acceptance
Economic No economic evidence was identified for this question.

considerations
The type of information and how it was delivered has an impact on the
patient’s decision to undertake surgery and how they perceived the referral
pathway.
This could be seen as capturing ‘process utility’, in other words, the non-
health benefits that consumers derive from healthcare programmes, such as
‘reassurance value’ arising from knowledge of a procedure. If a person
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exhibits anxiety because they are not reassured by a process of care, then
this anxiety could be measured as impairment of their psychological
wellbeing and therefore be a measurable component of their health related
quality of life. This could be captured within the patient’s response to the
anxiety and depression domain of the EQ-5D.
From a synthesis of the themes captured by the review, it becomes apparent

that if more information were provided for all these aspects, then this could
affect the effectiveness of the surgery by influencing, positively, the anxiety
domain of the EQ-5D, especially if people knew they had made the right
choice.
In terms of the impact on costs, if these themes only differ in terms of

content, rather than delivery, then offering more information is likely to have
little impact upon costs. However, if the delivery does differ, then this could
impact upon costs. For example, with regard to information on the surgical
procedure, people noted that they would have liked more information on
the alternatives and the less invasive options. This may involve more time
with a healthcare professional (as opposed to say a leaflet) and possibly the
use of decision aids in order to identify the best option for that patient, thus
further consultation time will result in additional cost.
The GDG considered the themes in the recommendation to be important

enough to justify the cost of the time spent by the health care professional
discussing these topics.
Quality of The quality of the seven qualitative studies included was assessed using a
Update 2014
evidence modified version of the NICE qualitative studies appraisal framework. The
limitations of the mixed methods cross sectional and longitudinal studies
were also highlighted in the evidence report. The GDG noted that caution
was required when interpreting data from those studies conducted in a non-
UK setting. For example, the US healthcare system places several biases on
the nature of its qualitative evidence. Overall most weight was given to the
UK studies due to their applicable setting and well reported nature. It was
noted however that most studies were conducted at one site thus limiting
the applicability and transferability of their data to the wider OA population.
Other The GDG discussed the findings of the review and noted that it would be
considerations important to ensure that patients were given adequate information to
support discussion to allow an informed choice to be made as to whether
joint surgery would be an appropriate management strategy for their
particular circumstances.
They noted that care should be individually tailored and different people
may follow different pathways dependent upon their individual
circumstances. For the most part, the GDG felt that people should at least
have been offered the core interventions outlined in this guideline although
they recognised for some, consideration of surgery may be a more
immediate treatment option with some equally choosing not to have surgery
once they have discussed the pertinent issues.
The GDG chose to add into their recommendation discussion of local

pathways of care as they were aware that these varied across the country
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and that people should have tailored information to consider.
The GDG also discussed the desirability to be able to inform patients of

patient reported outcome measures data. Patient Reported Outcome
Measures (PROMs) assess the quality of care delivered to NHS patients from
the patient perspective. PROMs calculate the health gains after surgical
treatment using pre- and post-operative surveys and are currently being
collected for hip and knee surgery. The GDG are aware of work being
Update 2014
undertaken by a team at the University of Oxford looking at predictors of
good outcome for lower limb joint arthroplasty and hope that this work may
be available for future iterations of this guideline to consider when thinking
about optimal timing of referral to surgery. In the meantime, the GDG felt
that the existing CG59 recommendations related to referral for surgery
remained pertinent and important in practice and selected two of the
recommendations made in CG59 as key priorities for implementation as they
felt that there were still some improvements to be made in the NHS in this
regard.
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Patient follow-up
13 Patient follow-up
13.1 Introduction
The GDG considered the scope inclusion area of follow up and recognised that appropriate
recommendations for this process are already in place through existing recommendations in the NICE
Patient experience in adult service guideline (CG138). They noted that these recommendations
emphasise that follow up should be tailored to individual need and should address the patient’s
knowledge and understanding about their condition and their view of their need for treatment. Such
opportunities should be individualised in approach, including a review of the person’s individual
needs and circumstances and should happen at intervals agreed with them. The GDG agreed it would
be helpful to cross reference these recommendations as part of this update of CG59 but did not feel
that there would be value in a review question linked to appropriate follow up for OA given the
generic and appropriate recommendations that could easily be linked to the OA population.
CG59 recommended three core treatments which should be considered for every person with
osteoarthritis: education, advice and information access; strengthening exercise aerobic fitness
training; and weight loss if overweight/obese. The GDG noted that recent work on quality indicators
has been completed in the areas of exercise and physiotherapy, education and information and
weight management.134. The GDG were aware that uptake of core treatments was currently limited
in the NHS with room for improvement.
The aims of these reviews were therefore to examine the added value of reinforcement techniques
Update 2014
on core treatment modalities and which different methods of content and delivery of reinforcement
improve outcomes in OA and to identify if any particular groups would benefit from this
reinforcement as part of any regular follow-up or review.
13.1.1 What is the clinical and cost effectiveness of regular follow-up or review in reinforcing core
treatments (information, education, exercise, weight reduction) care in the management
of OA?

Intervention/s Reinforcement of core treatment (information, education, exercise, weight reduction)
as part of regular review/follow-up
Comparison/s No reinforcement of core treatment
Outcomes  Global joint pain (WOMAC, VAS, or NRS pain subscale, WOMAC for knee and hip
only, AUSCAN subscale for hand)
 Function (WOMAC function subscale for hip or knee or equivalent such as AUSCAN
function subscale or Cochin or FIHOA for hand and change from baseline)
 Stiffness (WOMAC stiffness score change from baseline)
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Patient follow-up
 Improvement in depression/ psychological outcomes

Study design  Systematic reviews and meta-analyses
 RCTs
 Conference abstracts for unpublished trials
Update 2014
Six RCTs40,182,189,372,389,487 and one systematic review363 were included in the review. Evidence from
these are summarised in the clinical GRADE evidence profile below (Table 285). See also the study
No evidence was found for the time to joint replacement outcome.
CG59 previously looked at efficacy of self-management and core treatment. Therefore, this review
has not included studies which specifically looked at the effectiveness of self-management strategies
or elements of core treatment (information, education, exercise or weight loss) unless these were
compared in a review/follow up scenario after the main intervention was delivered.
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Patient follow-up

Study Population Intervention/comparison Outcomes Comments
Weight Loss
Bliddal Primary knee Intensive low energy diet WOMAC pain: Favours 1 year
40
2011 OA by ACR (LED) maintained by Dietician Review Blinded outcome
n=95 criteria in frequent consultations (44 (p=0.02) assessment
rheumatology visits) with a dietician WOMAC stiffness: NS
outpatients in versus difference
Denmark Control: minimal attention WOMAC function: NS
(5 visits) difference
AEs: constipation (9%),
flatulence (11%) in
intervention group
Exercise
Pisters Hip and Knee Exercise with additional Exercise with booster Huang papers
363
2007 OA booster adherence sessions sessions favours deemed of low
3RCTs with versus decrease in pooled pain methodological
‘booster control after long term and quality
sessions’ ‘booster’ follow up
Huang
2003
Huang
2005
Messier
Update 2014
1997
n=355
Delivery of Care
Wetzels Mild hip or Supporting patients self- Dutch AIMS2 QOL: NS 6 months
487
2008 knee OA in management with a difference in physical,
n=104 primary care practice-based nurse (3 symptoms, social or
patients in the sessions) affect domains.
Netherlands versus
Control: Education leaflet
Rosemann Hip or knee OA Group 1: GP’s had two 2 Group 1 versus control: 9 months
389
2007 in primary care interactive OA education NS difference in AIMS2 Cluster RCT
n=1021 in Germany sessions QOL in all domains,
versus number of patients
Group 2: GP’s had same referred to orthopaedics
interactive sessions + Group 2 versus control:
practice nurse 4 weekly NS difference in AIMS2
telephone f/u QOL in upper body and
versus affect domains
Control: Usual care Favours group 2 in lower
body, symptoms and
social domains
More patients referred
to orthopaedics in group
2
More prescriptions of
paracetamol in group 1
and group 2 compared
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Patient follow-up
Study Population Intervention/comparison Outcomes Comments

to usual care
Hay Adults over 55 Enhanced pharmacy review NS difference in 12 months
182
2006 with knee pain facilitated by pharmacist WOMAC pain, function, Excluded
n=181 in primary care versus patient global patients with
in the UK Control: Information leaflet assessment or number inflammatory
and one off phone call from of patient meeting arthritis, acute
rheumatology nurse OMERACT-OARSI trauma or
responder criteria malignancy
versus
between enhanced
Community physiotherapy pharmacy review and
(not reported here)) control
NS difference in Hospital
Update 2014
anxiety and depression
scale
Ravaud Knee OA by Three standardised Favours standardised 1 year open

372
2009 ACR criteria in consultations with a consultation for SF 12 cluster
n= 327 primary care rheumatologist with Physical Function and randomised trial
referred to reinforcement principles WOMAC function.
rheumatology versus NS difference in NS pain.
in France Control: three usual care “No AEs were reported
sessions with a during the study”
rheumatologist
189
Hill 2009 OA in any joint Clinical nurse specialist clinic VAS pain: NS difference 48 weeks
n=100 referred from versus NS difference in AIMS2 Single blind
primary to junior doctor hospital clinic psychological domain
secondary care but favours CNS clinic
in the UK for physical function
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Patient follow-up
Table 285: Weight loss maintained by dietician versus minimal attention control at one year: Bliddal 201240
Absolute effect Quality Importance

Weight loss Relative
No of Risk of Other Minimal attention Standardised/Mean
Design Inconsistency Indirectness Imprecision maintained by Risk
studies bias considerations control (n) Difference (S/MD)
dietician (n) (95% CI)
(95% CI)
WOMAC pain (follow-up 1 years; measured with: WOMAC pain subscale; Better indicated by lower values) Bliddall 2012
b
Update 2014
1 randomised very no serious no serious serious none 44 45 - SMD 0.49 lower + CRITICAL
a
trials serious inconsistency indirectness (0.91 to 0.06 lower) VERY
LOW
WOMAC stiffness (follow-up 1 years; measured with: WOMAC stiffness subscale; Better indicated by lower values) Bliddall 2012
b
a
higher) LOW
WOMAC function (follow-up 1 years; measured with: WOMAC function subscale; Better indicated by lower values) Bliddall 2012
b
a
higher) LOW

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Patient follow-up
Table 286: Exercise with booster sessions versus control: Pisters 2007363
Absolute effect Quality Importance

Relative
No of Risk of Other Exercise with Standardised Mean
Design Inconsistency Indirectness Imprecision Control Risk
studies bias considerations booster sessions Difference (SMD)
(95% CI)
(95% CI)
Pooled pain (follow-up “long term” > 6 months; Better indicated by higher values) Pisters 2007
1 Systematic very very serious no serious serious None Generic Inverse Variance - SMD 1.70 higher (0.31 + IMPORTANT
a b c
Review serious inconsistency indirectness imprecision Pooled data (n=355) higher to 3.09 higher) VERY
Update 2014
LOW
downgraded by two increments if the degree of inconsistency was deemed very serious (I squared 75% or more). Pooled pain at long term follow up was sub grouped by quality of study. This
sub-grouping strategy failed to remove heterogeneity. Inconsistent outcomes were therefore re-analysed using a random effects model, rather than the default fixed effect model used initially
for all outcomes. The point estimate and 95% CIs given in the grade table and forest plots are those derived from the new random effects analysis.
Table 287: Practice nurse reinforcement versus education leaflet control at 6 months Wetzels 2008487

Quality Importance
No of Risk of Other Practice Nurse Education Relative

Design Inconsistency Indirectness Imprecision Absolute effect
studies bias considerations reinforcement (n) leaflet control Risk

447
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Patient follow-up
(n) (95% CI)

Standardised Mean
Difference (SMD)
(95% CI)
Dutch AIMS2: Physical (follow-up 6 months; Better indicated by lower values) Wetzels 2008
b
1 randomised very no serious no serious serious none 51 53 - SMD 0.18 lower (0.56 ++ IMPORTANT
a
LOW
Dutch AIMS2: Symptoms (follow-up 6 months; Better indicated by lower values) Wetzels 2008
1 randomised very no serious no serious no serious none 51 53 - SMD 0.01 lower (0.39 ++ IMPORTANT
a
Dutch AIMS2: Social (follow-up 6 months; Better indicated by lower values) Wetzels 2008
Update 2014
b
1 randomised very no serious no serious serious none 51 53 - SMD 0.2 lower (0.58 + IMPORTANT
a
LOW
Dutch AIMS2: Affect (follow-up 6 months; Better indicated by lower values) Wetzels 2008
b
a
LOW
Table 288: GP OA training versus usual care control at 9 months Rosemann 2007389

Quality Importance
No of Design Risk of Inconsistency Indirectness Imprecision Other GP OA Usual care Relative Absolute effect

448
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Patient follow-up
studies bias considerations training (n) control (n) (95% CI)

Standardised Mean
Difference (SMD)
(95% CI)
German AIMS2: Lower Body (follow-up 9 months; Better indicated by higher values) Rosemann 2007
a
1 randomised serious no serious no serious no serious none 261 258 - SMD 0.08 higher (0.09 +++ IMPORTANT
trials inconsistency indirectness imprecision lower to 0.25 higher) MODERATE
German AIMS2: Upper Body (follow-up 9 months; Better indicated by higher values) Rosemann 2007
a
German AIMS2: Symptoms (follow-up 9 months; Better indicated by higher values) Rosemann 2007
Update 2014
a
German AIMS2: Affect (follow-up 9 months; Better indicated by higher values) Rosemann 2007
a
1 randomised serious no serious no serious no serious none 261 258 - SMD 0.04 lower (0.22 +++ IMPORTANT
German AIMS2: Social (follow-up 9 months; Better indicated by higher values) Rosemann 2007
a
Percentage of patients requiring a prescription of paracetamol (follow-up 9 months) Rosemann 2007

a
1 randomised serious no serious no serious no serious none 261 258 - SMD 0.29 higher (0.12 to +++ IMPORTANT
trials inconsistency indirectness imprecision 0.46 higher) MODERATE
Referrals to orthopaedics (follow-up 9 months) Rosemann 2007

a

449
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Patient follow-up
Table 289: GP OA training plus practice nurse phone-call reinforcement versus usual care control at 9 months: Rosemann 2007389
Other Absolute effect Quality Importance

considerations Relative
No of Risk of GP Training + Usual care Standardised Mean
Design Inconsistency Indirectness Imprecision Risk
studies bias Phone call (n) control (n) Difference (SMD)
(95% CI)
(95% CI)
German AIMS2: Lower Body (follow-up 9 months; Better indicated by higher values) Rosemann 2007
Update 2014
a
1 randomised serious no serious no serious no serious none 276 258 - SMD 0.17 higher (0 to 0.34 +++ IMPORTANT
trials inconsistency indirectness imprecision higher) MODERATE
German AIMS2: Upper Body (follow-up 9 months; Better indicated by higher values) Rosemann 2007
a
German AIMS2: Symptoms (follow-up 9 months; Better indicated by higher values) Rosemann 2007
a
German AIMS2: Affect (follow-up 9 months; Better indicated by higher values) Rosemann 2007
a
German AIMS2: Social (follow-up 9 months; Better indicated by higher values) Rosemann 2007
a

450
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Patient follow-up
Percentage of patients requiring a prescription of paracetamol (follow-up 9 months) Rosemann 2007

a
Referrals to orthopaedics (follow-up 9 months) Rosemann 2007

a
Table 290: Pharmacy review versus advice leaflet control at 12 months 182
Update 2014
Absolute effect Importan

Quality
ce
No of Risk of Other Pharmacy Advice leaflet Relative Risk Standardised/Mean
Design Inconsistency Indirectness Imprecision
studies bias considerations review (n) control (n) (95% CI) Difference (S/MD)
(95% CI)
WOMAC pain (follow-up 12 months; Better indicated by lower values) Hay 2006
a
1 randomised serious no serious no serious no serious none 94 87 - SMD 0.16 higher (0.14 ++ CRITICAL
E
WOMAC function (follow-up 12 months; Better indicated by lower values) Hay 2006
a
1 randomised serious no serious no serious no serious none 92 89 - SMD 0.04 lower (0.33 ++ CRITICAL
E
PGA: Number of patients reporting 'better' or 'much better' (follow-up 12 months) Hay 2006

451
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Patient follow-up
a b
1 randomised serious no serious no serious Serious none 32/94 22/89 RR 1.38 (0.87 94 more per 1000 (from 32 ++ IMPORTA
trials inconsistency indirectness (34%) (24.7%) to 2.18) fewer to 292 more) LOW NT
Number of patients meeting OMERACT-OARSI Responder Criteria (follow-up 12 months) Hay 2006
a b
1 randomised serious no serious no serious very serious none 25/93 24/86 RR 0.96 (0.6 11 fewer per 1000 (from ++ IMPORTA
trials inconsistency indirectness (26.9%) (27.9%) to 1.55) 112 fewer to 153 more) LOW NT
Hospital Anxiety and Depression Scale - Depression subscale (follow-up 12 months; Better indicated by lower values) Hay 2006
a
1 randomised serious no serious no serious no serious none 92 87 - MD 0.01higher (0.69 lower ++ IMPORTA
trials inconsistency indirectness imprecision to 0.71 higher) MODERAT NT
E
Hospital Anxiety and Depression Scale - Anxiety Subscale (follow-up 12 months; Better indicated by lower values) Hay 2006
a
1 randomised serious no serious no serious no serious none 92 87 - MD 0.23 lower (1.08 lower ++ IMPORTA
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trials inconsistency indirectness imprecision to 0.62 higher) MODERAT NT
E
Table 291: Standardised consultation versus usual care control at one year: Ravaud 2009372
Absolute effect
Quality Importance
Relative
No of Risk of Other Standardised Usual care Standardised Mean
Design Inconsistency Indirectness Imprecision Risk
studies bias considerations consultation (n) control (n) Difference (SMD)
(95% CI)
(95% CI)

452
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Patient follow-up
NRS pain (follow-up 12 months; Better indicated by lower values) Ravaud 2009
1 randomised very no serious no serious no serious none 145 181 - SMD 0.19 lower (0.41 + IMPORTANT
a
WOMAC function (follow-up 12 months; Better indicated by lower values) Ravaud 2009
1 randomised very no serious no serious no serious none 144 176 - SMD 0.26 lower (0.48 + CRITICAL
a
trials serious inconsistency indirectness imprecision to 0.04 lower) LOW
Patient global assessment of disease activity (follow-up 12 months; Better indicated by lower values) Ravaud 2009
b
a
LOW
Update 2014
SF 12: Physical Function (follow-up 12 months; Better indicated by higher values) Ravaud 2009
b
1 randomised very no serious no serious serious none 129 147 - SMD 0.28 higher (0.05 + IMPORTANT
a
trials serious inconsistency indirectness to 0.52 higher) VERY
LOW
Table 292: Clinical nurse specialist versus junior doctor hospital clinic at 48 weeks: Hill 2009189
Quality Importance
Clinical nurse Junior doctor Relative Absolute effect
No of Risk of Other
Design Inconsistency Indirectness Imprecision specialist clinic hospital clinic Risk Standardised Mean
studies bias considerations
(n) (n) (95% CI)
Difference (SMD)

453
Osteoarthritis
Patient follow-up
(95% CI)
VAS pain (follow-up 48 weeks; Better indicated by lower values): Hill 2009
a
1 randomised serious no serious no serious no serious none 51 49 - SMD 0.03 higher (0.36 ++ IMPORTANT
Update 2014
AIMS 2: Physical Function (follow-up 48 weeks; Better indicated by lower values): Hill 2009
a b
1 randomised serious no serious no serious serious none 51 49 - SMD 0.42 lower (0.82 ++ IMPORTANT
trials inconsistency indirectness to 0.02 lower) LOW
AIMS2: Psychological (follow-up 48 weeks; Better indicated by lower values): Hill 2009
a
1 randomised serious no serious no serious no serious none 51 49 - SMD 0.1 lower (0.49 +++ IMPORTANT

454
Osteoarthritis
Patient follow-up
No economic evidence was identified comparing regular follow-up or review aimed at reinforcing
core treatments with no reinforcement of core treatment.
Unit costs
In the absence of recent UK cost-effectiveness analysis, relevant unit costs are provided to aid
consideration of cost effectiveness. These are examples of the costs of providing reinforcement
sessions based on the professional involved.
Table 293: Resource use and costs associated with reinforcement of core treatments
Resource use Cost (a)
GP appointment £36 per surgery consultation (£185 per hour)
Practice based nurse £51 per hour of face‐to‐face contact
Rheumatologist (b) £162 per contract hour
Dietician (c) £35 per hour
Exercise sessions(d) £34 per hour
94
(a) Costs are from PSSRU 2012 . All costs include qualifications.
(b) Assume consultant rate
(c) Hospital based
(d) Assume community physiotherapist
Update 2014
As well as the time of professional, patients may be given additional resources such as
leaflets/reading material; support may also be provided via telephone as an alternative to face to
face contact. The frequency and length of appointments will obviously have an impact on the costs
and resources for the NHS.
Clinical
Weight Loss
One study with 95 participants suggested dietician maintained weight loss may be similarly effective
compared to minimal attention control in improving WOMAC pain (VL) stiffness (VL) or function (VL)
at one year follow up.
Exercise
One systematic review containing three relevant studies with 355 participants favoured exercise with
booster sessions compared to control in reduction of pooled pain at “long term follow up” (> 6
months) (VL) although there was uncertainty surrounding the effect.
Delivery of Care
One study with 104 participants suggested three sessions with a practice nurse may be similarly
effective compared to education leaflet control in improving AIMS2 quality of life; physical (VL),
symptoms (L), social (VL) or affect (VL) domains at 6 months follow up.
Osteoarthritis
Patient follow-up
One study with 1021 participants suggested training GPs with 2 sessions may be similarly effective
compared to usual care control in improving AIMS2 quality of life; lower body (M), upper body (M),
symptoms (M), affect (M) and social (M) domains, and there may be no difference in reducing
numbers of paracetamol prescriptions (M) or referrals to orthopaedics (M) at 9 months follow up.
One study with 1021 participants suggested training GPs with 2 sessions and practice nurse phone
call reinforcement may be similarly effective compared to usual care control in improving AIMS2
quality of life; lower body (M), upper body (M), symptoms (M), affect (M) and social (M) domains, or
in reducing numbers of paracetamol prescriptions (M) or referrals to orthopaedics (M) at 9 months
follow up.
One study with 181 participants suggested enhanced pharmacy review improved patient global
assessment (L) compared to advice leaflet control at 12 months follow up although there was some
uncertainty surrounding the effect. .Enhanced pharmacy review and advice leaflet control may be
similarly effective in reducing WOMAC pain (M) and HADS anxiety and depression subscales (M) or
improving WOMAC function (M), and there may be no difference in the number of patients meeting
OMERACT-OARSI responder criteria (L) at 12 months follow up.
One study with 327 participants suggested a standardised consultation model may be similarly
effective compared to usual care control in reducing NRS pain (L); improving WOMAC function (L), SF
12 quality of life: physical function domain (VL) or patient global assessment (VL) at one year follow
up.
Once study with 100 participants suggested a clinical nurse specialist clinic may be similarly effective
compared to a junior doctor hospital clinic in reducing VAS pain (M) or improving AIMS2 quality of
life; physical domain (L) or psychological domain (M) at 48 weeks follow up.
Update 2014
Economic
No relevant economic evaluations were identified.
41.Offer regular reviews to all people with symptomatic osteoarthritis.

Agree the timing of the reviews with the person (see also
recommendation 42). Reviews should include:
 monitoring the person’s symptoms and the ongoing impact of the
condition on their everyday activities and quality of life
 monitoring the long-term course of the condition
 discussing the person’s knowledge of the condition, any concerns
they have, their personal preferences and their ability to access
services
 reviewing the effectiveness and tolerability of all treatments
 support for self-management. [new 2014]
42.Consider an annual review for any person with one or more of the
following:
 troublesome joint pain
Recommendations  more than one joint with symptoms
Osteoarthritis
Patient follow-up
 more than one comorbidity

 taking regular medication for their osteoarthritis. [new 2014]
43.Apply the principles in Patient experience in adult NHS services (NICE

clinical guidance 138) with regard to an individualised approach to
healthcare services and patient views and preferences. [new 2014]
Relative values of The GDG considered pain and function to be the critical outcomes for
different decision-making. Other important outcomes were stiffness, the OMERACT
outcomes OARSI responder criteria and the patient’s global assessment.
CG59 recommended that core treatment (weight loss, exercise and patient
Trade off between
education) should be considered for every person with OA. In this partial
clinical benefits
update, the GDG were interested in determining whether the effectiveness
and harms
of the core treatment could be reinforced through appropriate follow-up.
The review identified evidence on the reinforcement of weight loss, exercise
and on the differing strategies of delivery of the reinforcement.
Weight loss
One study40 suggested that dietician maintained weight loss may be similarly
effective to minimal attention control for improving WOMAC pain, stiffness
or function at one year follow up. However, the quality of the evidence was
very low.
Exercise
One systematic review 363 favoured exercise with booster sessions compared
to control in reducing pooled pain of differing scales at follow up (> 6
months) although there was uncertainty surrounding the effect, and the
quality of the evidence was very low.
Delivery of care
Update 2014
All studies included in the review showed similar efficacy for differing care
delivery strategies compared to their control arm for the outcomes
reviewed. These strategies included extra GP training, practice nurse
telephone follow up, enhanced pharmacy review and use of standardised
consultation models. The quality of this evidence ranged from moderate to
very low.
Overall, the GDG noted the lack of efficacy, compared to an appropriate
control, of core treatment reinforcement strategies across the included
trials. They noted the possible benefit of booster sessions of exercise therapy
but noted the large variability in quality of exercise sessions across the NHS
currently. This variability is based on factors including location, length and
frequency of sessions and session facilitators.
The GDG agreed that follow up should be both patient-led and healthcare
professional-led. The GDG discussed how patient follow up is essential to
monitor patient’s condition and agreed on developing consensus
recommendations to maximise benefit to the patient and to minimise the
harms associated with a lack of follow up.
Economic The cost of the review will be dependent on the health care professional
considerations involved. For example a GP costs approximately £185 per hour (£36 per
consultation), a practice based nurse costs £51 per hour, and a dietician costs
£35 per hour.
Osteoarthritis
Patient follow-up
In terms of cost effectiveness, a trade-off is present as the reinforcement of

core treatment as part of follow up may be providing additional benefit.
Potential benefits could include; delaying surgery, or needing less medication
as a result, which would lead to potential future cost savings. Additionally,
quality of life could be improved if these sessions are more effective than
usual care or standard follow up in terms of managing pain and improving
function. As an example; the cost of time with a dietician or exercise sessions
were similar to the cost of a shorter GP consultation. If they provide
additional benefit compared to a GP consultation then these booster
sessions are likely to be a more cost effective way of reviewing or following
up patients.
Through consensus the GDG felt an appropriate recommendation should

include information on what should be included in a follow up review and
criteria for who should be followed up including the timing of a review. The
GDG were cautious about making strict recommendations on the frequency
of follow up given the lack of data about clinical benefits as well as no
economic analysis. Quantifying a time period as routine would have cost and
resource implications, however the GDG felt that stating follow up should be
at least annually fitted in well with guidelines of other long term conditions.
Quality of Meta-analysis was not performed due to the heterogeneity in the types and
evidence strategies of core treatment reinforcement reviewed. Cluster RCTs were
included in the review. The recruitment of health care professionals prior to
randomisation broke allocation concealment, and this led to outcomes
quality being downgraded.
The quality of the evidence varied between moderate and very low due to
the heterogeneous nature of studies included in the review. Quality was an
Update 2014
influencing factor when deciding not to advocate any particular strategy
found in the trials but instead to formulate consensus based
recommendations.
Other The GDG chose to cross refer to the principles outlined in the relevant
considerations recommendations regarding follow-up from the NICE Patient experience in
adult service guideline (CG138). They particularly noted that this guideline
recommended that services should be tailored to the individual person and
include a regular review of the patient’s needs and circumstances.
The GDG discussed the uncertainty of the benefits of any particular type of
reinforcement intervention, the low quality of the evidence and the lack of
economic analysis. The GDG, through a process of discussion, reached a
consensus about the key aspects that should be included in any follow up
and the timing of reviews.
These aspects included supporting people to self-manage their condition,

reviewing treatment efficacy and tolerability as well as gaining an overview
of all current medications being taken to manage symptoms. The latter was
considered especially important in the context of frequently used, over-the-
counter medications. Having an overview of all medication recorded
accurately, including over-the-counter use, that enables healthcare staff to
monitor a person’s condition appropriately is especially valuable (see
Osteoarthritis
Patient follow-up
recommendation 26). Such monitoring could include tests to assess kidney

function, blood pressure measurement or to look for blood loss due to
gastrointestinal bleeding.
Despite the lack of evidence in terms of particular models for the

reinforcement of core treatments, the GDG felt it important to recommend
that patients should be encouraged to continue to undertake muscle
strengthening and aerobic exercise and to reduce weight if appropriate.
Such approaches are complex behaviour change interventions and the GDG
felt that these interventions needed to be reinforced as part of any
opportunistic review. No evidence was found to target reinforcement at any
particular sub-group of people with osteoarthritis.
The GDG noted that people living with this chronic condition often struggle
to manage the pain associated with it and that consequently has a limiting
impact on everyday activity and quality of life. They discussed the
opportunities to provide support to people in facilitating self management.
They identified a number of key components that should be included in any
review opportunity that would ensure that appropriate interventions could
be discussed and offered depending on disease progression or the
effectiveness or tolerability of current treatments and that would facilitate a
partnership approach between clinician and person regarding the monitoring
of the long term course of their condition.
The GDG also felt that an annual review should be considered for certain
groups of people to ensure best care. The GDG agreed by consensus that
those groups should include (but not be limited to) those patients who are
taking regular medications or who have troublesome joint pain or multiple
joint involvement (groups that are often prescribed high levels of
medication) or multiple comorbidities (a group where polypharmacy is
common).
Update 2014
Importantly, people with OA are often taking multiple medications, usually
NSAIDs, and the GDG were aware that it is current practice within the NHS to
offer regular review of the need for long term treatment in line with advice
in the British National Formulary. They noted that the Quality Outcomes
Framework (QOF) also included (until April 2013) at least 15 month reviews
for patients on any repeat medications. It was removed from QOF in April
2013 because it was felt that General Practitioners were now doing this as a
matter of good practice. It seems therefore that, at least in part, annual
review or similar is established practice for people taking regular medications
including those for the management of OA pain and so this periodic review
would also be appropriate for people taking any medications to manage their
osteoarthritis pain. It would be practical if at all possible to combine this
annual medication review with a review along the lines recommended here
for the groups specified.
The GDG were aware that those patients who have ‘troublesome’ joint pain
were regular attenders at primary care. People with multiple joint
involvement are often prescribed high levels of medication and in discussion
the GDG felt that at least annual review in this group is required to ensure
appropriate medication prescription and review as outlined above. Similarly,
those with more than one comorbidity, for example cardiovascular disease
Osteoarthritis
Patient follow-up
or diabetes or chronic kidney disease, may be in receipt of polypharmacy

which would again require monitoring and review. The GDG noted that given
the prevalence of OA in the older population, this particular issue is likely to
be quite common. The GDG also felt that it would be appropriate to offer
more frequent review to any patients in whom monitoring (following a
review of the impact of their regular medication) indicated, for example, a
drop in haemoglobin or a reduction in kidney function to ensure appropriate
care.
The GDG acknowledged that guidelines on the management of other long

term conditions such as diabetes , cardiovascular disease and chronic
obstructive pulmonary disease in the NHS already include the frequency of
patient follow-up (annually), and felt that, in order to be consistent and
equitable, people with OA should also be offered the opportunity for an
annual review and this should be an aspirational target for the NHS. They
Update 2014
also noted that the NHS mandate112 has made enhancing the quality of life
for people with chronic conditions a priority and determined that everyone
with long-term conditions, including people with mental health problems,
should be offered a personalised care plan that reflects their preferences and
agreed decisions. The GDG felt that their recommendations supported the
relevant government priorities in this regard.
Research recommendations
Due to the lack of evidence, the GDG agreed to draft a research

recommendation regarding the optimum timing and content of review and
follow-up for people with osteoarthritis and how this may relate to
structured pathways of care. For further information please see appendix M.
13.2 Which patients with OA will benefit the most from reinforcement of
core treatment as part of regular follow-up/review?
No evidence was retrieved for this review question.
Osteoarthritis
Reference list
14 Reference list
1 NIH consensus conference: Total hip replacement. NIH Consensus Development Panel on Total
Hip Replacement. JAMA. 1995; 273(24):1950-1956
2 Ajzen I, Fishbein M. Understanding attitudes and predicting social behaviour. USA: Prentice
Hall; 1980
3 Algozzine GJ, Stein GH, Doering PL. Trolamine salicylate cream in osteoarthritis of the knee.
JAMA. 1982; 247(9):1311-1313
4 Altman RD, Akermark C, Beaulieu AD, Schnitzer T. Efficacy and safety of a single intra-articular
injection of non-animal stabilized hyaluronic acid (NASHA) in patients with osteoarthritis of the
knee. Osteoarthritis and Cartilage. 2004; 12(8):642-649
5 Altman RD, Aven A, Holmburg CE, Pfeifer LM, Sack M, Young GT. Capsaicin cream 0.025% as
monotherapy for osteoarthritis: A double-blind study. Seminars in Arthritis and Rheumatism.
1994; 23(Suppl 3):25-33
6 Altman RD, Rosen JE, Bloch DA, Hatoum HT, Korner P. A double-blind, randomized, saline-
controlled study of the efficacy and safety of EUFLEXXA for treatment of painful osteoarthritis
of the knee, with an open-label safety extension (the FLEXX trial). Seminars in Arthritis and
Rheumatism. 2009; 39(1):1-9
7 Altman RD, Zinsenheim JR, Temple AR, Schweinle JE. Three-month efficacy and safety of
acetaminophen extended-release for osteoarthritis pain of the hip or knee: a randomized,
double-blind, placebo-controlled study. Osteoarthritis and Cartilage. 2007; 15(4):454-461
8 Amadio P, Cummings D. Evaluation of acetaminophen in the management of osteoarthritis of

the knee. Current Therapeutic Research - Clinical and Experimental. 1983; 34(1):59-66
9 Amin AK, Clayton RA, Patton JT, Gaston M, Cook RE, Brenkel IJ. Total knee replacement in
morbidly obese patients. Results of a prospective, matched study. Journal of Bone and Joint
Surgery - British Volume. 2006; 88(10):1321-1326
10 Andrews CJ, Cohen L, Crail RB, Douch G, Sheldon MG, Wray KA. A trial of Fortagesic and
Paramol 118 in osteoarthritis. Journal of International Medical Research. 1976; 4(6):432-434
11 Arcury TA, Gesler WM, Cook HL. Meaning in the use of unconventional arthritis therapies.
American Journal of Health Promotion. 1999; 14(1):7-15
12 Arensi F. Comparison of efficacy and therapeutic safety of two treatments based on hyaluronic
acid (Go-On and Hyalgan) in knee osteoarthritis. Minerva Ortopedica e Traumatologica. 2006;
57(3):105-111
13 Arthritis and Musculoskeletal Alliance. Standards of care for people with osteoarthritis.
London. ARMA, 2004. Available from: www.arma.uk.net
14 Arthritis Care. OA nation. London. Arthritis Care, 2004. Available from:

www.arthritiscare.org.uk

461
Osteoarthritis
Reference list
15 Arthritis Research Campaign. Arthritis:the big picture. London. Arthritis Research Campaign,
2002. Available from: www.arc.org.uk
16 Atchia I, Kane D, Reed MR, Isaacs JD, Birrell F. Efficacy of a single ultrasound-guided injection
for the treatment of hip osteoarthritis. Annals of the Rheumatic Diseases. 2011; 70(1):110-116
17 Auerbach B. Cross-linked hyaluronic acid in the treatment of osteoarthritis of the knee--results

of a prospective randomized trial. Zentralblatt Für Chirurgie. 2002; 127(10):895-899
18 Bahadir C, Onal B, Dayan VY, Gürer N. Comparison of therapeutic effects of sodium

hyaluronate and corticosteroid injections on trapeziometacarpal joint osteoarthritis. Clinical
Rheumatology. 2009; 28(5):529-533
19 Baker K, Goggins J, Xie H, Szumowski K, LaValley M, Hunter DJ et al. A randomized crossover

trial of a wedged insole for treatment of knee osteoarthritis. Arthritis and Rheumatism. 2007;
56(4):1198-1203
20 Baker KG, Robertson V, Duck F. A review of therapeutic ultrasound: biophysical effects.

Physical Therapy. 2001; 81:1351-1358
21 Ballantyne PJ, Gignac MA, Hawker GA. A patient-centered perspective on surgery avoidance for
hip or knee arthritis: lessons for the future. Arthritis and Rheumatism. 2007; 57(1):27-34
22 Barton GR, Sach TH, Jenkinson C, Avery AJ, Doherty M, Muir KR. Do estimates of cost-utility
based on the EQ-5D differ from those based on the mapping of utility scores? Health and
Quality of Life Outcomes. 2008; 6:51
23 Battisti E, Piazza E, Rigato M, Nuti R, Bianciardi L, Scribano A et al. Efficacy and safety of a
musically modulated electromagnetic field (TAMMEF) in patients affected by knee
osteoarthritis. Clinical and Experimental Rheumatology. 2004; 22(5):568-572
24 Baxter D. Low intensity laser therapy. In: Kitchen S, Bazin S (eds), Clayton's electrotherapy, 10
edition. London: WB Saunders, 1996: 197-217
25 Bayramoglu M, Karatas M, Cetin N, Akman N, Sozay S, Dilek A. Comparison of two different

viscosupplements in knee osteoarthritis -- a pilot study. Clinical Rheumatology. 2003;
22(2):118-122
26 Bellamy N, Bourne R, Campbell J, Wells G. Intra-articular corticosteroids for osteoarthritis of

the knee. Cochrane Database of Systematic Reviews. 2006; Issue 2:CD005328.
DOI:10.1002/14651858.CD005328.pub2.
27 Bellamy N, Campbell J, Welch V, Gee TL, Bourne R, Wells GA. Viscosupplementation for the
treatment of osteoarthritis of the knee. Cochrane Database of Systematic Reviews. 2006; Issue
2:CD005321. DOI:10.1002/14651858.CD005321.pub2
28 Belza B, Topolski T, Kinne S, Patrick DL, Ramsey SD. Does adherence make a difference? Results
from a community-based aquatic exercise program. Nursing Research. 2002; 51(5):285-291
29 Bennell KL, Hinman RS, Metcalf BR. Efficacy of physiotherapy management of knee joint
osteoarthritis: a randomised, double blind, placebo controlled trial. Annals of the Rheumatic
Diseases. 2005; 64(6):906-912

462
Osteoarthritis
Reference list
30 Bensen WG, Fiechtner JJ, McMillen JI. Treatment of osteoarthritis with celecoxib, a
cyclooxygenase-2 inhibitor: a randomized controlled trial. Mayo Clinic Proceedings. 1999;
74(11):1095-1105
31 Berenbaum F, Grifka J, Cazzaniga S, D'Amato M, Giacovelli G, Chevalier X et al. A randomised,

double-blind, controlled trial comparing two intra-articular hyaluronic acid preparations
differing by their molecular weight in symptomatic knee osteoarthritis. Annals of the
Rheumatic Diseases. 2012; 71(9):1454-1460
32 Berman BM, Lao L, Langenberg P, Lee WL, Gilpin AM, Hochberg MC. Effectiveness of
acupuncture as adjunctive therapy in osteoarthritis of the knee: a randomized, controlled trial.
Annals of Internal Medicine. 2004; 141(12):901-910
33 Berry H. Controlled trial of a knee support ('Genutrain') in patients with osteoarthritis of the
knee. European Journal of Rheumatology and Inflammation. 1992; 12(3):30-34
34 Bianchi M, Broggini M, Balzarini P, Baratelli E, Ferrario P, Panerai AE et al. Effects of tramadol

on synovial fluid concentrations of substance P and interleukin-6 in patients with knee
osteoarthritis: comparison with paracetamol. International Immunopharmacology. 2003; 3(13-
14):1901-1908
35 Bierma-Zeinstra SM, Oster JD, Bernsen RM, Verhaar JA, Ginai AZ, Bohnen AM. Joint space
narrowing and relationship with symptoms and signs in adults consulting for hip pain in
primary care. Journal of Rheumatology. 2002; 29(8):1713-1718
36 Bingham CO, Sebba AI, Rubin BR, Ruoff GE, Kremer J, Bird S et al. Efficacy and safety of
etoricoxib 30 mg and celecoxib 200 mg in the treatment of osteoarthritis in two identically
designed, randomized, placebo-controlled, non-inferiority studies. Rheumatology. 2007;
46(3):496-507
37 Bird HA, Hill J, Stratford ME, Fenn GC, Wright V. A double-blind cross-over study comparing the
analgesic efficacy of tramadol with pentazocine in patients with osteoarthritis. Journal of Drug
Development and Clinical Practice. 1995; 7(3):181-188
38 Bjordal JM, Klovning A, Ljunggren AE, Slordal L. Short-term efficacy of pharmacotherapeutic

interventions in osteoarthritic knee pain: A meta-analysis of randomised placebo-controlled
trials. European Journal of Pain. 2007; 11(2):125-138
39 Black C, Clar C, Henderson R, MacEachern C, McNamee P, Quayyum Z et al. The clinical

effectiveness of glucosamine and chondroitin supplements in slowing or arresting progression
of osteoarthritis of the knee: a systematic review and economic evaluation. Health Technology
Assessment. 2009; 13(52)
40 Bliddal H, Leeds AR, Stigsgaard L, Astrup A, Christensen R. Weight loss as treatment for knee
osteoarthritis symptoms in obese patients: 1-year results from a randomised controlled trial.
Annals of the Rheumatic Diseases. 2011; 70(10):1798-1803
41 Borjesson M, Robertson E, Weidenhielm L, Mattsson E, Olsson E. Physiotherapy in knee

osteoarthrosis: effect on pain and walking. Physiotherapy Research International. 1996;
1(2):89-97
42 Boureau F, Delecoeuillerie G, Orvain J. Comparative study of the efficacy and tolerance of 2

dosages of the paracetamol 400 mg codeine 25 mg association versus paracetamol 1000 mg in

463
Osteoarthritis
Reference list
non-inflammatory rheumatic pain. Rhumatologie - Revue International De Rhumatologie. 1990;

20(1):41-47
43 Bourgeois P, Chales G, Dehais J, Delcambre B, Kuntz JL, Rozenberg S. Efficacy and tolerability of
chondroitin sulfate 1200 mg/day vs chondroitin sulfate 3 x 400 mg/day vs placebo.
Osteoarthritis and Cartilage. 1998; 6 Suppl A:25-30
44 Bradley JD, Heilman DK, Katz.B.P. Tidal irrigation as treatment for knee osteoarthritis: a sham-
controlled, randomized, double-blinded evaluation. Arthritis and Rheumatism. 2002;
46(1):100-108
45 Brenes GA, Rapp SR, Rejeski WJ, Miller ME. Do optimism and pessimism predict physical
functioning? Journal of Behavioral Medicine. 2002; 25(3):219-231
46 Brismee JM, Paige RL, Chyu MC, Boatright JD, Hagar JM, McCaleb JA et al. Group and home-
based tai chi in elderly subjects with knee osteoarthritis: a randomized controlled trial. Clinical
Rehabilitation. 2007; 21(2):99-111
47 Brosseau L, Gam A, Harman K, Morin M, Robinson VA, Shea BJ et al. Low level laser therapy
(Classes I, II and III) for treating osteoarthritis. Cochrane Database of Systematic Reviews. 2006;
Issue 3:CD002046. DOI:10.1002/14651858.CD002046.pub2
48 Brosseau L, Welch V, Wells G, Tugwell P, de Bie R, Gam A et al. Low level laser therapy for
osteoarthritis and rheumatoid arthritis: a metaanalysis. Journal of Rheumatology. 2000;
27(8):1961-1969
49 Brosseau L, Yonge KA, Welch V, Marchand S, Judd M, Wells GA et al. Thermotherapy for
treatment of osteoarthritis. Cochrane Database of Systematic Reviews. 2003; Issue
4:CD004522. DOI:10.1002/14651858.CD004522
50 Brouwer RW, van Raaij TM, Jakma TT, Verhagen AP, Verhaar JAN, Bierma-Zeinstra SMA. Braces
and orthoses for treating osteoarthritis of the knee. Cochrane Database of Systematic Reviews.
2005; Issue 1:CD004020. DOI:10.1002/14651858.CD004020.pub2
51 Brouwer RW, van Raaij TM, Verhaar JA, Coene LN, Bierma ZS. Brace treatment for
osteoarthritis of the knee: a prospective randomized multi-centre trial. Osteoarthritis and
Cartilage. 2006; 14(8):777-783
52 Bruyere O, Scholtissen S, Neuprez A, Hiligsmann M, Toukouki A, Reginster JY. Impact of

chondroitin sulphate on health utility in patients with knee osteoarthritis: towards economic
analysis. Journal of Medical Economics. 2009; 12(4):356-360
53 Bucsi L, Poor G. Efficacy and tolerability of oral chondroitin sulfate as a symptomatic slow-
acting drug for osteoarthritis (SYSADOA) in the treatment of knee osteoarthritis. Osteoarthritis
and Cartilage. 1998; 6 Suppl A:31-36
54 Buszewicz M, Rait G, Griffin M, Nazareth I, Patel A, Atkinson A et al. Self management of

arthritis in primary care: randomised controlled trial. BMJ. 2006; 333(7574):879
55 Calfas K.J., Kaplan RM, Ingram RE. One-year evaluation of cognitive-behavioral intervention in
osteoarthritis. Arthritis Care and Research. 1992; 5(4):202-209

464
Osteoarthritis
Reference list
56 Callaghan MJ, Oldham JA, Hunt J. An evaluation of exercise regimes for patients with
osteoarthritis of the knee: A single-blind randomized controlled trial. Clinical Rehabilitation.
1995; 9(3):213-218
57 Callaghan MJ, Whittaker PE, Grimes S, Smith L. An evaluation of pulsed shortwave on knee
osteoarthritis using radioleucoscintigraphy: a randomised, double blind, controlled trial. Joint,
Bone, Spine: Revue Du Rhumatisme. 2005; 72(2):150-155
58 Caracciolo B, Giaquinto S. Determinants of the subjective functional outcome of total joint

arthroplasty. Archives of Gerontology and Geriatrics. 2005; 41(2):169-176
59 Carr AJ, Donovan JL. Why doctors and patients disagree. British Journal of Rheumatology. 1998;
37(1):1-4
60 Cepeda MS, Camargo F, Zea C, Valencia L. Tramadol for osteoarthritis. Cochrane Database of
Systematic Reviews. 2006; Issue 3:CD005522. DOI:10.1002/14651858.CD005522.pub2
61 Chakrabarti AJ, Robinson AHN, Gallagher P. De la Caffiniere thumb carpometacarpal

replacements. 93 cases at 6 to 16 years follow-up. Journal of Hand Surgery - British Volume.
1997; 22 B(6):695-698
62 Chamberlain MA, Care G. Physiotherapy in osteoarthrosis of the knees. A controlled trial of

hospital versus home exercises. International Rehabilitation Medicine. 1982; 4(2):101-106
63 Chan FK, Wong VW, Suen BY, Wu JC, Ching JY, Hung LC et al. Combination of a cyclo-
oxygenase-2 inhibitor and a proton-pump inhibitor for prevention of recurrent ulcer bleeding
in patients at very high risk: a double-blind, randomised trial. Lancet. 2007; 369(9573):1621-
1626
64 Chan GN, Smith AW. Changes in knee moments with contralateral versus ipsilateral cane usage
in females with knee osteoarthritis. Clinical Biomechanics. 2005; 20(4):396-404
65 Chan WP, Lang P, Stevens MP, Sack K, Majumdar S, Stoller DW et al. Osteoarthritis of the knee:
comparison of radiography, CT, and MR imaging to assess extent and severity. American
Journal of Roentgenology. 1991; 157(4):799-806
66 Chang RW, Falconer J. A randomized, controlled trial of arthroscopic surgery versus closed-
needle joint lavage for patients with osteoarthritis of the knee. Arthritis and Rheumatism.
1993; 36(3):289-296
67 Cheing GL, Hui-Chan CW. Analgesic effects of transcutaneous electrical nerve stimulation and
interferential currents on heat pain in healthy subjects. Journal of Rehabilitation Medicine.
2003; 35:62-68
68 Cheing GL, Hui-Chan CWY. Would the addition of TENS to exercise training produce better
physical performance outcomes in people with knee osteoarthritis than either intervention
alone? Clinical Rehabilitation. 2004; 18(5):487-497
69 Cheing GL, Huichan CWY, Chan KM. Does four weeks of TENS and/or isometric exercise
produce cumulative reduction of osteoarthritic knee pain? Clinical Rehabilitation. 2002;
16(7):749-760
70 Cheing GL, Tsui AY, Lo SK, Hui-Chan CW. Optimal stimulation duration of TENS in the
management of osteoarthritic knee pain. Journal of Rehabilitation Medicine. 2003; 35:62-68

465
Osteoarthritis
Reference list
71 Cheung KW, Chung SL, Chung KY, Chiu KH. Patient perception and knowledge on total joint
replacement surgery. Hong Kong Medical Journal. 2013; 19(1):33-37
72 Chevalier X, Jerosch J, Goupille P, van Dijk N, Luyten FP, Scott DL et al. Single, intra-articular
treatment with 6 ml hylan G-F 20 in patients with symptomatic primary osteoarthritis of the
knee: a randomised, multicentre, double-blind, placebo controlled trial. Annals of the
73 Chikanza IC, Clarke B. A comparative study of the efficacy and toxicity of etodolac and
naproxen in the treatment of osteoarthritis. British Journal of Clinical Practice. 1994; 48(2):67-
69
74 Chodosh J, Morton SC, Mojica W, Maglione M, Suttorp MJ, Hilton L et al. Meta-analysis:
Chronic disease self-management programs for older adults. Annals of Internal Medicine. 2005;
143(6):427-438+I32
75 Christensen R, Bartels EM, Astrup A, Bliddal H. Effect of weight reduction in obese patients
diagnosed with knee osteoarthritis: a systematic review and meta-analysis. Annals of the
76 Cibere J, Kopec JA, Thorne A, Singer J, Canvin J, Robinson DB et al. Randomized, double-blind,
placebo-controlled glucosamine discontinuation trial in knee osteoarthritis. Arthritis Care and
Research. 2004; 51(5):738-745
77 Cibere J, Sayre EC, Guermazi A, Esdaile JM, Kopec J, Singer J et al. Do physical examinations
predict oa progression based on MRI? Results from the vancouver knee osteoarthritis
progression study. Osteoarthritis and Cartilage. 2011; 19:S148
78 Clegg DO, Reda DJ, Harris CL, Klein MA, O'Dell JR, Hooper MM et al. Glucosamine, chondroitin
sulfate, and the two in combination for painful knee osteoarthritis. New England Journal of
Medicine. 2006; 354(8):795-808
79 Cliborne AV, Wainner RS, Rhon DI, Judd CD, Fee TT, Matekel RL et al. Clinical hip tests and a
functional squat test in patients with knee osteoarthritis: reliability, prevalence of positive test
findings, and short-term response to hip mobilization. Journal of Orthopaedic and Sports
Physical Therapy. 2004; 34(11):676-685
80 Cochrane T, Davey RC, Matthes Edwards SM. Randomised controlled trial of the cost-
effectiveness of water-based therapy for lower limb osteoarthritis. Health Technology
Assessment. 2005;1
81 Cohen M, Wolfe R, Mai T, Lewis D. A randomized, double blind, placebo controlled trial of a
topical cream containing glucosamine sulfate, chondroitin sulfate, and camphor for
osteoarthritis of the knee. Journal of Rheumatology. 2003; 30(3):523-528
82 Cohen MM, Altman RD, Hollstrom R, Hollstrom C, Sun C, Gipson B. Safety and efficacy of intra-
articular sodium hyaluronate (Hyalgan) in a randomized, double-blind study for osteoarthritis
of the ankle. Foot and Ankle International. 2008; 29(7):657-663
83 Conrozier T. [Anti-arthrosis treatments: efficacy and tolerance of chondroitin sulfates (CS

4&6)]. Presse Medicale. 1998; 27(36):1862-1865
84 Conrozier T, Jerosch J, Beks P, Kemper F, Euller-Ziegler L, Bailleul F et al. Prospective, multi-

centre, randomised evaluation of the safety and efficacy of five dosing regimens of

466
Osteoarthritis
Reference list
viscosupplementation with hylan G-F 20 in patients with symptomatic tibio-femoral

osteoarthritis: a pilot study. Archives of Orthopaedic and Trauma Surgery. 2009; 129(3):417-
423
85 Conrozier T, Vignon E. Die Wirkung von Chondroitin sulfat bei der Behandlung der
Hüftgelenksarthrose: eine Doppelblindstudie gegen Placebo. Litera Rheumatologica. 1992;
14:69-75
86 Cook C, Pietrobon R, Hegedus E. Osteoarthritis and the impact on quality of life health
indicators. Rheumatology International. 2007; 27(4):315-321
87 Corben S and Rosen R. Self management for long term conditions: patients' perspectives on
the way ahead. London. King's Fund, 2005
88 Coulter A and Ellins J. Patient-focused interventions: a review of the evidence. London. Health
Foundation, 2006. Available from: http://www.health.org.uk/qquip/
89 Coupe VM, Veenhof C, van Tulder MW, Dekker J, Bijlsma JW, van den Ende CH. The cost
effectiveness of behavioural graded activity in patients with osteoarthritis of hip and/or knee.
90 Cox F, Stevenson F, and Britten N. A systematic review of communication between patients

and healthcare professionals about medicine taking and prescribing. London. Medicines
Partnership, 2004
91 Coyte PC, Hawker Croxford GR, Croxford R, Attard C, Wright JG. Variation in rheumatologists'
and family physicians' perceptions of the indications for and outcomes of knee replacement
surgery. Journal of Rheumatology. 1996; 23(4):730-738
92 Croft P. The 5% symptomatic OA prevalence. Personal communication: 2007
93 Cross MJ, March LM, Lapsley HM, Byrne E, Brooks PM. Patient self-efficacy and health locus of
control: relationships with health status and arthritis-related expenditure. Rheumatology.
2006; 45(1):92-96
94 Curtis L. Unit costs of health and social care. Canterbury: Personal Social Services Research
Unit, University of Kent; 2012. Available from:
http://www.pssru.ac.uk/archive/pdf/uc/uc2012/full-with-covers.pdf
95 Curtis SP, Bockow B, Fisher C, Olaleye J, Compton A, Ko AT et al. Etoricoxib in the treatment of
osteoarthritis over 52-weeks: A double-blind, active-comparator controlled trial. BMC
Musculoskeletal Disorders. 2005; 6:10p
96 Cushnaghan J, McCarthy C, Dieppe P. Taping the patella medially: a new treatment for
osteoarthritis of the knee joint? BMJ. 1994; 308(6931):753-755
97 D'Agostino MA, Conaghan PG, Le Bars M, Baron G, Grassi W, Martin-Mola E. EULAR report on
the use of ultrasonography in painful knee osteoarthritis. Part 1: prevalence of inflammation in
osteoarthritis. Annals of the Rheumatic Diseases. 2005; 64:1703-1709
98 Das A, Jr., Hammad TA. Efficacy of a combination of FCHG49 glucosamine hydrochloride,

TRH122 low molecular weight sodium chondroitin sulfate and manganese ascorbate in the
management of knee osteoarthritis. Osteoarthritis and Cartilage. 2000; 8(5):343-350

467
Osteoarthritis
Reference list
99 Dawes PT, Kirlew C, Haslock I. Saline washout for knee osteoarthritis: results of a controlled
study. Clinical Rheumatology. 1987; 6(1):61-63
100 Day R, Brooks P, Conaghan PG, Petersen M, Multicenter Trial Group. A double blind,
randomized, multicenter, parallel group study of the effectiveness and tolerance of
intraarticular hyaluronan in osteoarthritis of the knee. Journal of Rheumatology. 2004;
31(4):775-782
101 de Achaval S, Fraenkel L, Volk R, Cox V, Suarez-Almazor ME. Impact of a patient decision aid
with an interactive values component on decisional conflict associated with total knee
arthroplasty. Arthritis and Rheumatism. 2011; 63(10 SUPPL. 1)
102 de Achaval S, Fraenkel L, Volk RJ, Cox V, Suarez-Almazor ME. Impact of educational and patient
decision aids on decisional conflict associated with total knee arthroplasty. Arthritis Care and
Research. 2012; 64(2):229-237
103 De Jong OR, Hopman-Rock M, Tak EC. An implementation study of two evidence-based
exercise and health education programmes for older adults with osteoarthritis of the knee and
hip. Health Education Research. 2004; 19(3):316-325
104 De Leeuw JM, Villar RN. Obesity and quality of life after primary total knee replacement. Knee.
1998; 5(2):119-123
105 de Miguel ME, Cobo IT, Uson JJ, Bonilla HG, Martin ME. Clinical and ultrasonographic findings
related to knee pain in osteoarthritis. Osteoarthritis and Cartilage. 2006; 14(6):540-544
106 Deal CL, Schnitzer TJ, Lipstein E, Seibold JR, Stevens RM, Levy MD et al. Treatment of arthritis
with topical capsaicin: a double-blind trial. Clinical Therapeutics. 1991; 13(3):383-395
107 Degreef I, De Smet L. Predictors of outcome in surgical treatment for basal joint osteoarthritis
of the thumb. Clinical Rheumatology. 2006; 25(2):140-142
108 DeGroot IH, Uzunishvili S, Weir R, Al-omari A, Gomes B. Intra-articular injection of hyaluronic
acid is not superior to saline solution injection for ankle arthritis: A randomized, double-blind,
placebo-controlled study. Journal of Bone and Joint Surgery - American Volume. 2012; 94(1):2-
8
109 Demierre M, Castelao E, Piot-Ziegler C. The long and painful path towards arthroplasty: a
qualitative study. Journal of Health Psychology. 2011; 16(4):549-560
110 Department of Health. Self care - a real choice: Self care support- a practical option. London.
Department of Health, 2005. Available from:
http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidan
ce/DH_4100717
111 Department of Health. NHS reference costs 2009-2010. 2011. Available from:
http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidan
ce/DH_123459 [Last accessed: 1 August 2011]
112 Department of Health. The Mandate: a mandate from the government to the NHS
Commissioning Board: April 2013 to March 2015. London. Department of Health, 2013.
Available from: https://www.gov.uk/government/publications/the-nhs-mandate

468
Osteoarthritis
Reference list
113 Department of Work and Pensions. Opportunity age:meeting the challenges of aging in the
21st century Volume 1. London. HM Government, 2005
114 Dequeker J. Improvement in gastrointestinal tolerability of the selective cyclooxygenase (COX)-

2 inhibitor, meloxicam, compared with piroxicam: results of the Safety and Efficacy Large-scale
Evaluation of COX-inhibiting Therapies (SELECT) trial in osteoarthritis. British Journal of
Rheumatology. 1998; 37(9):946-951
115 Deyle GD, Henderson NE, Matekel RL. Effectiveness of manual physical therapy and exercise in
osteoarthritis of the knee. A randomized, controlled trial. Annals of Internal Medicine. 2000;
132(3):173-181
116 Deyle GD, Allison SC, Matekel RL, Ryder MG, Stang JM, Gohdes DD et al. Physical therapy
treatment effectiveness for osteoarthritis of the knee: a randomized comparison of supervised
clinical exercise and manual therapy procedures versus a home exercise program. Physical
Therapy. 2005; 85(12):1301-1317
117 Diracoglu D, Vural M, Baskent A, Dikici F, Aksoy C. The effect of viscosupplementation on

neuromuscular control of the knee in patients with osteoarthritis. Journal of Back and
Musculoskeletal Rehabilitation. 2009; 22(1):1-9
118 Dixon AS, Jacoby RK, Berry H, Hamilton EB. Clinical trial of intra-articular injection of sodium
hyaluronate in patients with osteoarthritis of the knee. Current Medical Research and Opinion.
1988; 11(4):205-213
119 Doherty M. Color atlas and text of osteoarthritis. USA: Mosby; 1995
120 Doherty M, Mazieres B, Le Bars M. EULAR recommendations for the treatment of osteoarthritis
of the knee in general practice [CD ROM]. Bristol-Myers Squibb/Laboratoires UPSA; 2003
121 Dolin SJ, Williams AC, Ashford N, George J, Pereira L, Perello A. Factors affecting medical
decision-making in patients with osteoarthritis of the hip: allocation of surgical priority.
Disability and Rehabilitation. 2003; 25(14):771-777
122 Dominkus M, Nicolakis M, Kotz R, Wilkinson FE, Kaiser RR, Chlud K. Comparison of tissue and
plasma levels of ibuprofen after oral and topical administration. Arzneimittel-Forschung. 1996;
46(12):1138-1143
123 Donovan JL, Blake DR. Qualitative study of interpretation of reassurance among patients
attending rheumatology clinics: "just a touch of arthritis, doctor?". BMJ. 2000; 320(7234):541-
544
124 Donovan JL, Blake DR, Fleming WG. The patient is not a blank sheet: lay beliefs and their
relevance to patient education. British Journal of Rheumatology. 1989; 28(1):58-61
125 Dosanjh S, Matta JM, Bhandari M, Anterior THA Research Collaborative. The final straw: a
qualitative study to explore patient decisions to undergo total hip arthroplasty. Archives of
Orthopaedic and Trauma Surgery. 2009; 129(6):719-727
126 Downe-Wamboldt B. Coping and life satisfaction in elderly women with osteoarthritis. Journal
of Advanced Nursing. 1991; 16(11):1328-1335
127 Dracoglu D, Aydin R, Baskent A, Celik A. Effects of kinesthesia and balance exercises in knee
osteoarthritis. Journal of Clinical Rheumatology. 2005; 11(6):303-310

469
Osteoarthritis
Reference list
128 Dreinhofer KE, Dieppe P, Sturmer T, Grober GD, Floren M, Gunther KP et al. Indications for
total hip replacement: comparison of assessments of orthopaedic surgeons and referring
physicians. Annals of the Rheumatic Diseases. 2006; 65(10):1346-1350
129 Duer A, Ostergaard M, Horslev-Petersen K, Vallo J. Magnetic resonance imaging and bone
scintigraphy in the differential diagnosis of unclassified arthritis. Annals of the Rheumatic
Diseases. 2008; 67(1):48-51
130 Duncan R, Peat G, Thomas E, Hay E, McCall I, Croft P. Symptoms and radiographic
osteoarthritis: not as discordant as they are made out to be? Annals of the Rheumatic
Diseases. 2007; 66(1):86-91
131 Duncan RC, Hay EM, Saklatvala J, Croft PR. Prevalence of radiographic osteoarthritis--it all
depends on your point of view. Rheumatology. 2006; 45(6):757-760
132 Dyson M. The effect of ultrasound on the rate of wound healing and the quality of scar tissue.
Proceedings of the International Symposium on Therapeutic Ultrasound 1981. Winnipeg: CPA.
2007;
133 Dziedzic K, Thomas E, Hill S, Wilkie R, Peat G, Croft PR. The impact of musculoskeletal hand
problems in older adults: findings from the North Staffordshire Osteoarthritis Project
(NorStOP). Rheumatology. 2007; 46(6):963-967
134 Edwards JJ, Dziedzic KS, Jordan KP, Jordan JL, Croft PR. Quality Indicators for the Primary Care
of Osteoarthritis: A Systematic Review. Annals of the Rheumatic Diseases. 2011; 70(Suppl
3):338
135 Elson DW, Brenkel IJ. Predicting Pain After Total Knee Arthroplasty. Journal of Arthroplasty.
2006; 21(7):1047-1053
136 Elwyn G, Edwards A, Kinnersley P. Shared decision-making in primary care: the neglected
second half of the consultation. British Journal of General Practice. 1999; 49(443):477-482
137 Escobar A, Quintana JM, Bilbao A, Azkarate J, Guenaga JI, Arenaza JC et al. Effect of patient
characteristics on reported outcomes after total knee replacement. Rheumatology. 2007;
46(1):112-119
138 Evcik D, Kavuncu V, Yeter A, Yigit I. The efficacy of balneotherapy and mud-pack therapy in
patients with knee osteoarthritis. Joint, Bone, Spine: Revue Du Rhumatisme. 2007; 74(1):60-65
139 Evcik D, Sonel B. Effectiveness of a home-based exercise therapy and walking program on
osteoarthritis of the knee. Rheumatology International. 2002; 22(3):103-106
140 Eyigor S, Hepguler S, Capaci K. A comparison of muscle training methods in patients with knee
osteoarthritis. Clinical Rheumatology. 2004; 23(2):109-115
141 Felson DT, Lawrence RC, Dieppe PA, Hirsch R, Helmick CG, Jordan JM et al. Osteoarthritis: new
insights. Part 1: the disease and its risk factors. Annals of Internal Medicine. 2000; 133(8):635-
646
142 Felson DT, McAlindon TE, Anderson JJ, Naimark A, Weissman BW, Aliabadi P et al. Defining
radiographic osteoarthritis for the whole knee. Osteoarthritis and Cartilage. 1997; 5(4):241-250

470
Osteoarthritis
Reference list
143 Ferreira VM, Sherman AM. The relationship of optimism, pain and social support to well-being
in older adults with osteoarthritis. Aging & Mental Health. 2007; 11(1):89-98
144 Fielden JM, Cumming JM, Horne JG, Devane PA, Slack A, Gallagher LM. Waiting for hip
arthroplasty: economic costs and health outcomes. Journal of Arthroplasty. 2005; 20:990-997
145 Fioravanti A, Valenti M, Altobelli E, Di Orio F, Nappi G, Crisanti A et al. Clinical efficacy and cost-
effectiveness evidence of spa therapy in osteoarthritis. The results of "Naiade" Italian Project.
Panminerva Medica. 2003; 45(3):211-217
146 Flanagan J, Casale FF, Thomas TL, Desai KB. Intra-articular injection for pain relief in patients
awaiting hip replacement. Annals of the Royal College of Surgeons of England. 1988; 70(3):156-
157
147 Fleischmann R, Sheldon E, Maldonado CJ, Dutta D, Yu S, Sloan VS. Lumiracoxib is effective in
the treatment of osteoarthritis of the knee: a prospective randomized 13-week study versus
placebo and celecoxib. Clinical Rheumatology. 2006; 25(1):42-53
148 Focht BC, Rejeski WJ, Ambrosius WT, Katula JA, Messier SP. Exercise, self-efficacy, and mobility
performance in overweight and obese older adults with knee osteoarthritis. Arthritis and
Rheumatism. 2005; 53(5):659-665
149 Foley A, Halbert J, Hewitt T, Crotty M. Does hydrotherapy improve strength and physical
function in patients with osteoarthritis--a randomised controlled trial comparing a gym based
and a hydrotherapy based strengthening programme. Annals of the Rheumatic Diseases. 2003;
62(12):1162-1167
150 Foster NE, Thomas E, Barlas P, Hill JC, Young J, Mason E et al. Acupuncture as an adjunct to
exercise based physiotherapy for osteoarthritis of the knee: randomised controlled trial. BMJ.
2007; 335(7617):436-440
151 Fraenkel L, Rabidou N, Wittink D, Fried T. Improving informed decision-making for patients
with knee pain. Journal of Rheumatology. 2007; 34(9):1894-1898
152 Fransen M, McConnell S, Bell M. Therapeutic exercise for people with osteoarthritis of the hip
or knee. A systematic review. Journal of Rheumatology. 2002; 29(8):1737-1745
153 Fransen M, Nairn L, Winstanley J, Lam P, Edmonds J. Physical activity for osteoarthritis
management: a randomized controlled clinical trial evaluating hydrotherapy or Tai Chi classes.
Arthritis and Rheumatism. 2007; 57(3):407-414
154 Frestedt JL, Walsh M, Kuskowski MA, Zenk JL. A natural mineral supplement provides relief
from knee osteoarthritis symptoms: a randomized controlled pilot trial. Nutrition Journal.
2008; 7:9
155 Fries JF, Bruce B. Rates of serious gastrointestinal events from low dose use of acetylsalicylic
acid, acetaminophen, and ibuprofen in patients with osteoarthritis and rheumatoid arthritis.
Journal of Rheumatology. 2003; 30(10):2226-2233
156 Fuchs S, Monikes R, Wohlmeiner A, Heyse T. Intra-articular hyaluronic acid compared with
corticoid injections for the treatment of rhizarthrosis. Osteoarthritis and Cartilage. 2006;
14(1):82-88

471
Osteoarthritis
Reference list
157 Gabay C, Medinger-Sadowski C, Gascon D, Kolo F, Finckh A. Symptomatic effects of chondroitin

4 and chondroitin 6 sulfate on hand osteoarthritis: a randomized, double-blind, placebo-
controlled clinical trial at a single center. Arthritis and Rheumatism. 2011; 63(11):3383-3391
158 Gana TJ, Pascual ML, Fleming RR. Extended-release tramadol in the treatment of osteoarthritis:
a multicenter, randomized, double-blind, placebo-controlled clinical trial. Current Medical
Research and Opinion. 2006; 22(7):1391-1401
159 Garfinkel MS, Schumacher HR, Jr., Husain A, Levy M, Reshetar RA. Evaluation of a yoga based
regimen for treatment of osteoarthritis of the hands. Journal of Rheumatology. 1994;
21(12):2341-2343
160 Gay MC, Philippot P, Luminet O. Differential effectiveness of psychological interventions for
reducing osteoarthritis pain: a comparison of Erikson hypnosis and Jacobson relaxation.
European Journal of Pain. 2002; 6(1):1-16
161 General Medical Council. Good Medical Practice. London. General Medical Council, 2006.
Available from: www.gmc-uk.org
162 Gibson JNA, White MD, Chapman VM, Strachan RK. Arthroscopic lavage and debridement for
osteoarthritis of the knee. Journal of Bone and Joint Surgery - British Volume. 1992; 74(4):534-
537
163 Gignac MA, Davis AM, Hawker G, Wright JG, Mahomed N, Fortin PR et al. "What do you
expect? You're just getting older": A comparison of perceived osteoarthritis-related and aging-
related health experiences in middle- and older-age adults. Arthritis and Rheumatism. 2006;
55(6):905-912
164 Gill GS, Mills D, Joshi AB. Mortality following primary total knee arthroplasty. Journal of Bone
and Joint Surgery - American Volume. 2003; 85(3):432-435
165 Giordano N, Fioravanti A, Papakostas P, Montella A, Giorgi G, Nuti R. The efficacy and
tolerability of glucosamine sulfate in the treatment of knee osteoarthritis: A randomized,
double-blind, placebo-controlled trial. Current Therapeutic Research - Clinical and
Experimental. 2009; 70(3):185-196
166 Golden HE, Moskowitz RW, Minic M. Analgesic efficacy and safety of nonprescription doses of
naproxen sodium compared with acetaminophen in the treatment of osteoarthritis of the
knee. American Journal of Therapeutics. 2004; 11(2):85-94
167 Gottesdiener K, Schnitzer T, Fisher C, Bockow B, Markenson J, Ko A et al. Results of a

randomized, dose-ranging trial of etoricoxib in patients with osteoarthritis. Rheumatology.
2002; 41(9):1052-1061
168 Goutallier D, van Driessche S, Manicom O, Ali ES, Bernageau J, Radier C. Influence of lower-limb
torsion on long-term outcomes of tibial valgus osteotomy for medial compartment knee
osteoarthritis. Journal of Bone and Joint Surgery - American Volume. 2006; 88(11):2439-2447
169 Grace D, Rogers J, Skeith K, Anderson K. Topical diclofenac versus placebo: a double blind,
randomized clinical trial in patients with osteoarthritis of the knee. Journal of Rheumatology.
1999; 26(12):2659-2663

472
Osteoarthritis
Reference list
170 Graf J, Neusel E, Schneider E, Niethard FU. Intra-articular treatment with hyaluronic acid in
osteoarthritis of the knee joint: a controlled clinical trial versus mucopolysaccharide
polysulfuric acid ester. Clinical and Experimental Rheumatology. 1993; 11(4):367-372
171 Green J, McKenna F, Redfern EJ, Chamberlain MA. Home exercises are as effective as
outpatient hydrotherapy for osteoarthritis of the hip. British Journal of Rheumatology. 1993;
32(9):812-815
172 Grifka JK. Efficacy and tolerability of lumiracoxib versus placebo in patients with osteoarthritis
of the hand. Clinical and Experimental Rheumatology. 2004; 22(5):589-596
173 Guermazi A, Niu J, Hayashi D, Roemer FW, Englund M, Neogi T et al. Prevalence of
abnormalities in knees detected by MRI in adults without knee osteoarthritis: Population based
observational study (Framingham Osteoarthritis Study). BMJ. 2012; 345:e5339
174 Hampson SE, Glasgow RE, Zeiss AM. Personal models of osteoarthritis and their relation to self-
management activities and quality of life. Journal of Behavioral Medicine. 1994; 17(2):143-158
175 Hampson SE, Glasgow RE, Zeiss AM. Coping with osteoarthritis by older adults. Arthritis Care
and Research. 1996; 9(2):133-141
176 Hampson SE, Glasgow RE, Zeiss AM, Birskovich SF, Foster L, Lines A. Self-management of
177 Harrysson OLA, Robertsson O, Nayfeh JF. Higher cumulative revision rate of knee arthroplasties
in younger patients with osteoarthritis. Clinical Orthopaedics and Related Research. 2004;
421:162-168
178 Hawel R. Comparison of the efficacy and tolerability of dexibuprofen and celecoxib in the
treatment of osteoarthritis of the hip. International Journal of Clinical Pharmacology and
Therapeutics. 2003; 41(4):153-164
179 Hawker GA, Wright JG, Coyte PC, Williams JI, Harvey B, Glazier R et al. Determining the need
for hip and knee arthroplasty: the role of clinical severity and patients' preferences. Medical
Care. 2001; 39(3):206-216
180 Hawkey C. Gastrointestinal tolerability of meloxicam compared to diclofenac in osteoarthritis

patients. International MELISSA Study Group. Meloxicam Large-scale International Study Safety
Assessment. British Journal of Rheumatology. 1998; 37(9):937-945
181 Hawkey C, Svoboda P. Gastroduodenal safety and tolerability of lumiracoxib compared with
Ibuprofen and celecoxib in patients with osteoarthritis. Journal of Rheumatology. 2004;
31(9):1804-1810
182 Hay EM, Foster NE, Thomas E, Peat G, Phelan M, Yates HE et al. Effectiveness of community
physiotherapy and enhanced pharmacy review for knee pain in people aged over 55 presenting
to primary care: Pragmatic randomised trial. BMJ. 2006; 333(7576):995-998
183 Hayes CW, Jamadar DA, Welch GW, Jannausch ML, Lachance LL, Capul DC et al. Osteoarthritis
of the knee: Comparison of MR imaging findings with radiographic severity measurements and
pain in middle-aged women. Radiology. 2005; 237(3):998-1007
184 Henderson EB, Smith EC, Pegley F, Blake DR. Intra-articular injections of 750 kD hyaluronan in
the treatment of osteoarthritis: a randomised single centre double-blind placebo-controlled

473
Osteoarthritis
Reference list
trial of 91 patients demonstrating lack of efficacy. Annals of the Rheumatic Diseases. 1994;
53(8):529-534
185 Herrero-Beaumont G, Ivorra JAR, Del Carmen Trabado M, Blanco FJ, Benito P, Martin-Mola E et
al. Glucosamine sulfate in the treatment of knee osteoarthritis symptoms: a randomized,
double-blind, placebo-controlled study using acetaminophen as a side comparator. Arthritis
and Rheumatism. 2007; 56(2):555-567
186 Heuts PH, de Bie R., Drietelaar M, Aretz K, Hopman-Rock M, Bastiaenen CH et al. Self-
management in osteoarthritis of hip or knee: a randomized clinical trial in a primary healthcare
setting. Journal of Rheumatology. 2005; 32(3):543-549
187 Heyneman CA, Lawless-Liday C, Wall GC. Oral versus topical NSAIDs in rheumatic diseases: a
comparison. Drugs. 2000; 60(3):555-574
188 Hill J, Bird H. Patient knowledge and misconceptions of osteoarthritis assessed by a validated
self-completed knowledge questionnaire (PKQ-OA). Rheumatology. 2007; 46(5):796-800
189 Hill J, Lewis M, Bird H. Do OA patients gain additional benefit from care from a clinical nurse
specialist?--a randomized clinical trial. Rheumatology. 2009; 48(6):658-664
190 Hinman RS, Bennell KL, Crossley KM. Immediate effects of adhesive tape on pain and disability
in individuals with knee osteoarthritis. Rheumatology. 2003; 42(7):865-869
191 Hinman RS, Crossley KM, McConnell J, Bennell KL. Efficacy of knee tape in the management of
osteoarthritis of the knee: blinded randomised controlled trial. BMJ. 2003; 327(7407):135
192 Hinman RS, Heywood SE, Day AR. Aquatic physical therapy for hip and knee osteoarthritis:
results of a single-blind randomized controlled trial. Physical Therapy. 2007; 87(1):32-43
193 Hoeksma HL, Dekker J, Ronday HK, Heering A, van der Lubbe N, Vel C et al. Comparison of
manual therapy and exercise therapy in osteoarthritis of the hip: a randomized clinical trial.
194 Hosie J. Efficacy and tolerability of meloxicam versus piroxicam in patients with osteoarthritis
of the hip or knee. A six-month double-blind study. Clinical Drug Investigation. 1997; 13(4):175-
184
195 Hosie J, Distel M, Bluhmki E. Meloxicam in osteoarthritis: A 6-month, double-blind comparison

with diclofenac sodium. British Journal of Rheumatology. 1996; 35(suppl 1):39-43
196 Huang M, Lin Y, Lee C, Yang R. Use of ultrasound to increase effectiveness of isokinetic exercise
for knee osteoarthritis. Archives of Physical Medicine and Rehabilitation. 2005; 86(8):1545-10
197 Huang MH, Chen CH, Chen TW, Weng MC, Wang WT, Wang YL. The effects of weight reduction
on the rehabilitation of patients with knee osteoarthritis and obesity. Arthritis Care and
Research. 2000; 13(6):398-405
198 Huang MH, Lin YS, Yang RC. A comparison of various therapeutic exercises on the functional
status of patients with knee osteoarthritis. Seminars in Arthritis and Rheumatism. 2003;
32(6):398-406
199 Huang MH, Yang RC, Lee CL, Chen TW, Wang MC. Preliminary results of integrated therapy for
patients with knee osteoarthritis. Arthritis and Rheumatism. 2005; 53(6):812-820

474
Osteoarthritis
Reference list
200 Huang TL, Chang CC, Lee CH, Chen SC, Lai CH, Tsai CL. Intra-articular injections of sodium
hyaluronate (Hyalgan©) in osteoarthritis of the knee. a randomized, controlled, double-blind,
multicenter trial in the Asian population. BMC Musculoskeletal Disorders. 2011; 12:221
201 Huang YC, Harbst K, Kotajarvi B, Hansen D, Koff MF, Kitaoka HB et al. Effects of ankle-foot
orthoses on ankle and foot kinematics in patient with ankle osteoarthritis. Archives of Physical
Medicine and Rehabilitation. 2006; 87(5):710-716
202 Hubbard MJ. Articular debridement versus washout for degeneration of the medial femoral
condyle. A five-year study. Journal of Bone and Joint Surgery - British Volume. 1996; 78(2):217-
219
203 Hudak PL, Clark JP, Hawker GA, Coyte PC, Mahomed NN, Kreder HJ et al. "You're perfect for the
procedure! Why don't you want it?" Elderly arthritis patients' unwillingness to consider total
joint arthroplasty surgery: a qualitative study. Medical Decision Making. 2002; 22(3):272-278
204 Hughes SL, Seymour RB, Campbell R, Pollak N, Huber G, Sharma L. Impact of the fit and strong
intervention on older adults with osteoarthritis. Gerontologist. 2004; 44(2):217-228
205 Hughes SL, Seymour RB, Campbell RT, Huber G, Pollak N, Sharma L et al. Long-term impact of
Fit and Strong! on older adults with osteoarthritis. Gerontologist. 2006; 46(6):801-814
206 Hulme J, Robinson V, de Bie R, Judd M, Tugwell P. Electromagnetic fields for the treatment of
osteoarthritis. Cochrane Database of Systematic Reviews. 2002; Issue 1:CD003523.
DOI:10.1002/14651858.CD003523
207 Hurley MV, Scott DL. Improvements in quadriceps sensorimotor function and disability of
patients with knee osteoarthritis following a clinically practicable exercise regime. British
208 Hurley MV, Walsh NE, Mitchell HL, Pimm TJ, Patel A, Williamson E et al. Clinical effectiveness of
a rehabilitation program integrating exercise, self-management, and active coping strategies
for chronic knee pain: a cluster randomized trial. Arthritis and Rheumatism. 2007; 57(7):1211-
1219
209 Iagnocco A, Meenagh G, Riente L, Filippucci E, Delle Sedie A, Scire CA et al. Ultrasound imaging
for the rheumatologist XXIX. Sonographic assessment of the knee in patients with
osteoarthritis. Clinical and Experimental Rheumatology. 2010; 28(5):643-646
210 Iannitti T, Rottigni V, Palmieri B. A pilot study to compare two different hyaluronic acid
compounds for treatment of knee osteoarthritis. International Journal of Immunopathology
and Pharmacology. 2012; 25(4):1093-1098
211 Iannotti JP, Norris TR. Influence of preoperative factors on outcome of shoulder arthroplasty
for glenohumeral osteoarthritis. Journal of Bone and Joint Surgery - American Volume. 2003;
85(2):251-258
212 Ike RW, Arnold WJ, Rothschild EW, Shaw HL. Tidal irrigation versus conservative medical
management in patients with osteoarthritis of the knee: A prospective randomized study.
213 Imamura K, Gair R, McKee M, Black N. Appropriateness of total hip replacement in the United
Kingdom. World Hospitals & Health Services. 1996; 32(2):10-14

475
Osteoarthritis
Reference list
214 Irani MS. Clinical and upper gastrointestinal effects of sulindac, indomethacin and paracetamol
plus dextropropoxyphene in patients with osteoarthritis. European Journal of Rheumatology
and Inflammation. 1980; 3(3):222-231
215 Itoh K, Hirota S, Katsumi Y, Ochi H, Kitakoji H. Trigger point acupuncture for treatment of knee
osteoarthritis - a preliminary RCT for a pragmatic trial. Acupuncture in Medicine. 2008;
26(1):17-26
216 Itoh K, Hirota S, Katsumi Y, Ochi H, Kitakoji H. A pilot study on using acupuncture and
transcutaneous electrical nerve stimulation (TENS) to treat knee osteoarthritis (OA). Chinese
Medicine. 2008; 3:2
217 Jain SA, Roach RT, Travlos J. Changes in body mass index following primary elective total hip
arthroplasty: Correlation with outcome at 2 years. Acta Orthopaedica Belgica. 2003; 69(5):421-
425
218 Jennings MB, Alfieri DM. A controlled comparison of etodolac and naproxen in osteoarthritis of
the foot. Lower Extremity. 1997; 4(1):43-48
219 Jensen EM, Ginsberg F. Tramadol versus dextropropoxyphene in the treatment of

osteoarthritis: A short term double-blind study. Drug Investigation. 1994; 8(4):211-218
220 Jinks C, Ong BN, Richardson J. A mixed methods study to investigate needs assessment for knee
pain and disability: population and individual perspectives. BMC Musculoskeletal Disorders.
2007; 8:59
221 Johnsen SP, Sorensen HT, Pedersen AB, Lucht U, Soballe K, Overgaard S. Patient-related
predictors of implant failure after primary total hip replacement in the initial, short- and long-
term: A nationwide Danish folow-up study including 36 984 patients. Journal of Bone and Joint
Surgery - British Volume. 2006; 88(10):1303-1308
222 Jones CA, Voaklander DC, Johnston DW, Suarez AM. The effect of age on pain, function, and
quality of life after total hip and knee arthroplasty. Archives of Internal Medicine. 2001;
161(3):454-460
223 Jordan K, Clarke AM, Symmons DP, Fleming D, Porcheret M, Kadam UT et al. Measuring disease
prevalence: a comparison of musculoskeletal disease using four general practice consultation
databases. British Journal of General Practice. 2007; 57(534):7-14
224 Jordan K, Jinks C, Croft P. A prospective study of the consulting behaviour of older people with
knee pain. British Journal of General Practice. 2006; 56(525):269-276
225 Jorgensen A, Stengaard-Pedersen K, Simonsen O, Pfeiffer-Jensen M, Eriksen C, Bliddal H et al.

Intra-articular hyaluronan is without clinical effect in knee osteoarthritis: A multicentre,
randomised, placebo-controlled, double-blind study of 337 patients followed for 1 year. Annals
of the Rheumatic Diseases. 2010; 69(6):1097-1102
226 Jubb RW, Tukmachi ES, Jones PW, Dempsey E, Waterhouse L, Brailsford S. A blinded
randomised trial of acupuncture (manual and electroacupuncture) compared with a non-
penetrating sham for the symptoms of osteoarthritis of the knee. Acupuncture in Medicine.
2008; 26(2):69-78

476
Osteoarthritis
Reference list
227 Juni P, Dieppe P, Donovan J, Peters T, Eachus J, Pearson N et al. Population requirement for
primary knee replacement surgery: a cross-sectional study. Rheumatology. 2003; 42(4):516-
521
228 Kahan A, Lleu PL, Salin L. Prospective randomized study comparing the medicoeconomic
benefits of Hylan GF-20 vs. conventional treatment in knee osteoarthritis. Joint, Bone, Spine:
Revue Du Rhumatisme. 2003; 70(4):276-281
229 Kahan A, Uebelhart D, De Vathaire F, Delmas PD, Reginster JY. Long-term effects of
chondroitins 4 and 6 sulfate on knee osteoarthritis: the study on osteoarthritis progression
prevention, a two-year, randomized, double-blind, placebo-controlled trial. Arthritis and
Rheumatism. 2009; 60(2):524-533
230 Kalay S. The effectiveness of intraarticular hyaluronic acid treatment in primary gonarthrosis.
Ankara: Ministry of Health, Republic of Turkey; 1997.
231 Kalunian KC, Moreland LW, Klashman DJ. Visually-guided irrigation in patients with early knee
osteoarthritis: a multicenter randomized, controlled trial. Osteoarthritis and Cartilage. 2000;
8(6):412-418
232 Karatosun V, Unver B, Ozden A, Ozay Z, Gunal I. Intra-articular hyaluronic acid compared to
exercise therapy in osteoarthritis of the ankle. A prospective randomized trial with long-term
follow-up. Clinical and Experimental Rheumatology. 2008; 26(2):288-294
233 Karlson EW, Daltroy LH, Liang MH, Eaton HE, Katz JN. Gender differences in patient preferences
may underlie differential utilization of elective surgery. American Journal of Medicine. 1997;
102(6):524-530
234 Kawasaki T, Kurosawa H, Ikeda H, Takazawa Y, Ishijima M, Kubota M et al. Therapeutic home
exercise versus intraarticular hyaluronate injection for osteoarthritis of the knee: 6-month
prospective randomized open-labeled trial. Journal of Orthopaedic Science. 2009; 14(2):182-
191
235 Keefe FJ, Blumenthal J. Effects of spouse-assisted coping skills training and exercise training in
patients with osteoarthritic knee pain: a randomized controlled study. Pain. 2004; 110(3):539-
549
236 Keen HI, Wakefield RJ, Conaghan PG. A systematic review of ultrasonography in osteoarthritis.
237 Kennedy LG, Newman JH, Ackroyd CE, Dieppe PA. When should we do knee replacements?
Knee. 2003; 10(2):161-166
238 Kerzberg EM, Roldan EJ, Castelli G, Huberman ED. Combination of glycosaminoglycans and
acetylsalicylic acid in knee osteoarthrosis. Scandinavian Journal of Rheumatology. 1987;
16(5):377-380
239 Kettunen JA, Kujala UM. Exercise therapy for people with rheumatoid arthritis and
osteoarthritis. Scandinavian Journal of Medicine & Science in Sports. 2004; 14(3):138-142
240 Kinds MB, Welsing PMJ, Vignon EP, Bijlsma JWJ, Viergever MA, Marijnissen ACA et al. A
systematic review of the association between radiographic and clinical osteoarthritis of hip and
knee. Osteoarthritis and Cartilage. 2011; 19(7):768-778

477
Osteoarthritis
Reference list
241 King's Fund. Social care needs and outcomes: a background paper for the Wanless Review.
London. King's Fund, 2005
242 Kivitz AJ, Moskowitz RW, Woods E. Comparative efficacy and safety of celecoxib and naproxen
in the treatment of osteoarthritis of the hip. Journal of International Medical Research. 2001;
29(6):467-479
243 Kjaersgaard AP, Nafei A, Skov O, Madsen F, Andersen HM, Kroner K et al. Codeine plus
paracetamol versus paracetamol in longer-term treatment of chronic pain due to osteoarthritis
of the hip. A randomised, double-blind, multi-centre study. Pain. 1990; 43(3):309-318
244 Klaber Moffett JA, Richardson PH, Frost H, Osborn A. A placebo controlled double blind trial to
evaluate the effectiveness of pulsed short wave therapy for osteoarthritic hip and knee pain.
Pain. 1996; 67(1):121-127
245 Kornaat PR, Bloem JL, Ceulemans RYT, Riyazi N, Rosendaal FR, Nelissen RG et al. Osteoarthritis
of the knee: association between clinical features and MR imaging findings. Radiology. 2006;
239(3):811-817
246 Koutroumpas AC, Alexiou IS, Vlychou M, Sakkas LI. Comparison between clinical and
ultrasonographic assessment in patients with erosive osteoarthritis of the hands. Clinical
Rheumatology. 2010; 29(5):511-516
247 Kroll TL, Richardson M, Sharf BF, Suarez-Almazor ME. "Keep on truckin'" or "It's got you in this
little vacuum": race-based perceptions in decision-making for total knee arthroplasty. Journal
of Rheumatology. 2007; 34(5):1069-1075
248 Kul-Panza E, Berker N. Is hyaluronate sodium effective in the management of knee

osteoarthritis? A placebo-controlled double-blind study. Minerva Medica. 2010; 101(2):63-72
249 Kuptniratsaikul V, Tosayanonda O, Nilganuwong S, Thamalikitkul V. The efficacy of a muscle

exercise program to improve functional performance of the knee in patients with
osteoarthritis. Journal of the Medical Association of Thailand. 2002; 85(1):33-40
250 L'Hirondel JL. Klinische Doppelblind-Studie mit oral verabreichtem Chondroitin sulfatgegen
Placebo bei der tibiofemoralen Gonarthrose (125 patients). Litera Rheumatologica. 1992;
14:77-84
251 Laborde JM, Powers MJ. Life satisfaction, health control orientation, and illness-related factors
in persons with osteoarthritis. Research in Nursing & Health. 1985; 8(2):183-190
252 Lai KC, Chu KM, Hui WM, Wong BC, Hu WH, Wong WM et al. Celecoxib compared with
lansoprazole and naproxen to prevent gastrointestinal ulcer complications. American Journal of
Medicine. 2005; 118(11):1271-1278
253 Lansdown H, Howard K, Brealey S, Macpherson H. Acupuncture for pain and osteoarthritis of
the knee: a pilot study for an open parallel-arm randomised controlled trial. BMC
Musculoskeletal Disorders. 2009; 10:130
254 Lastowiecka E, Bugajska J, Najmiec A, Rell BM, Bownik I, Jedryka GA. Occupational work and
quality of life in osteoarthritis patients. Rheumatology International. 2006; 27(2):131-139
255 Lau EM, Symmons DP, Croft P. The epidemiology of hip osteoarthritis and rheumatoid arthritis
in the Orient. Clinical Orthopaedics and Related Research. 1996;(323):81-90

478
Osteoarthritis
Reference list
256 LaValley MP, McAlindon TE, Chaisson CE, Levy D, Felson DT. The validity of different definitions
of radiographic worsening for longitudinal studies of knee osteoarthritis. Journal of Clinical
Epidemiology. 2001; 54(1):30-39
257 Lee PB, Kim YC, Lim YJ, Lee CJ, Sim WS, Ha CW et al. Comparison between high and low
molecular weight hyaluronates in knee osteoarthritis patients: Open-label, randomized,
multicentre clinical trial. Journal of International Medical Research. 2006; 34(1):77-87
258 Lefler C, Armstrong WJ. Exercise in the treatment of osteoarthritis in the hands of the elderly.
Clinical Kinesiology. 2004; 58(2):1-6
259 Lehmann R. Efficacy and tolerability of lumiracoxib 100 mg once daily in knee osteoarthritis: a
13-week, randomized, double-blind study vs. placebo and celecoxib. Current Medical Research
and Opinion. 2005; 21(4):517-526
260 Leung AT, Malmstrom K. Efficacy and tolerability profile of etoricoxib in patients with
osteoarthritis: A randomized, double-blind, placebo and active-comparator controlled 12-week
efficacy trial. Current Medical Research and Opinion. 2002; 18(2):49-58
261 Lev-Ari S, Miller E, Maimon Y, Rosenblatt Y, Mendler A, Hasner A et al. Delayed effect of
acupuncture treatment in OA of the knee: A blinded, randomized, controlled trial. Evidence-
Based Complementary and Alternative Medicine. 2011; 2011
262 Levy E, Ferme A, Perocheau D, Bono I. Socioeconomic costs of osteoarthritis in France. Revue
Du Rhumatisme. 1993; 60(6 Pt 2):63S-67S
263 Lim BW. A comparative study of open and closed kinetic chain exercise regimes in patients with
knee osteoarthritis. Physiotherapy Singapore. 2002; 5(2):34-40
264 Lin J, Zhang W, Jones A, Doherty M. Efficacy of topical non-steroidal anti-inflammatory drugs in
the treatment of osteoarthritis: meta-analysis of randomised controlled trials. BMJ. 2004;
329(7461):324
265 Linden B, Distel M, Bluhmki E. A double-blind study to compare the efficacy and safety of
meloxicam 15 mg with piroxicam 20 mg in patients with osteoarthritis of the hip. British
Journal of Rheumatology. 1996; 35(suppl 1):35-38
266 Lingard EA, Katz JN, Wright EA, Sledge CB, Kinemax Outcomes Group. Predicting the outcome
of total knee arthroplasty. Journal of Bone and Joint Surgery - American Volume. 2004; 86-
A(10):2179-2186
267 Lopes Vaz A. Double-blind clinical evaluation of the relative efficacy of ibuprofen and
glucosamine sulphate in the management of osteoarthrosis of the knee in out-patients.
Current Medical Research and Opinion. 1982; 8(3):145-149
268 Lord J, Victor C, Littlejohns P, Ross FM, Axford JS. Economic evaluation of a primary care-based
education programme for patients with osteoarthritis of the knee. Health Technology
Assessment. 1999; 3(23):1-55
269 Lund B. A double-blind, randomized, placebo-controlled study of efficacy and tolerance of

meloxicam treatment in patients with osteoarthritis of the knee. Scandinavian Journal of
Rheumatology. 1998; 27(1):32-37

479
Osteoarthritis
Reference list
270 Lundsgaard C, Dufour N, Fallentin E, Winkel P, Gluud C. Intra-articular sodium hyaluronate 2 mL

versus physiological saline 20 mL versus physiological saline 2 mL for painful knee
osteoarthritis: a randomized clinical trial. Scandinavian Journal of Rheumatology. 2008;
37(2):142-150
271 MacDonald CW, Whitman JM, Cleland JA, Smith M, Hoeksma HL. Clinical outcomes following
manual physical therapy and exercise for hip osteoarthritis: A case series. Journal of
Orthopaedic and Sports Physical Therapy. 2006; 36(8):588-599
272 Maetzel A, Krahn M, Naglie G. The cost effectiveness of rofecoxib and celecoxib in patients
with osteoarthritis or rheumatoid arthritis. Arthritis Care and Research. 2003; 49(3):283-292
273 Maillefert JF, Hudry C. Laterally elevated wedged insoles in the treatment of medial knee
osteoarthritis: a prospective randomized controlled study. Osteoarthritis and Cartilage. 2001;
9(8):738-745
274 Maisiak R, Austin J, Heck L. Health outcomes of two telephone interventions for patients with
rheumatoid arthritis or osteoarthritis. Arthritis and Rheumatism. 1996; 39(8):1391-1399
275 Malaise M, Marcolongo R, Uebalhart D, Vignon E. Efficacy and tolerabilityof 800 mg oral
chondroitin 4&6 sulfate in the treatment of knee osteoarthritis: a randomised, double-blind,
multicentre study versus placebo. Litera Rheumatologica. 1999; 24:31-42
276 Mancuso CA, Ranawat CS, Esdaile JM, Johanson NA, Charlson ME. Indications for total hip and
total knee arthroplasties. Results of orthopaedic surveys. Journal of Arthroplasty. 1996;
11(1):34-46
277 Mangione KK, McCully K. The effects of high-intensity and low-intensity cycle ergometry in
older adults with knee osteoarthritis. Journals of Gerontology Series A-Biological Sciences &
Medical Sciences. 1999; 54(4):M184-M190
278 Manheimer E, Cheng K, Linde K, Lao L, Yoo J, Wieland S et al. Acupuncture for peripheral joint
DOI:10.1002/14651858.CD001977.pub2
279 Mann C, Gooberman-Hill R. Health care provision for osteoarthritis: concordance between
what patients would like and what health professionals think they should have. Arthritis Care
and Research. 2011; 63(7):963-972
280 Mann WC, Hurren D, Tomita M. Assistive devices used by home-based elderly persons with
arthritis. American Journal of Occupational Therapy. 1995; 49(8):810-820
281 March L, Irwig L, Schwarz J, Simpson J, Chock C, Brooks P. n of 1 trials comparing a non-
steroidal anti-inflammatory drug with paracetamol in osteoarthritis. BMJ. 1994;
309(6961):1041-1045
282 Martin D. Interferential therapy for pain control. In: Kitchen S, Bazin S (eds), Clayton's
electrotherapy 10E, London: WB Saunders, 1996: 306-315
283 Martin JG, Rodriguez LP, Mora CD, Torres RR, Gomez FP, Pellico LG. Liquid nitrogen
cryotherapy effect on gait and pain in subjects with osteoarthritis of the knee. Europa
Medicophysica. 1998; 34(1):17-24

480
Osteoarthritis
Reference list
284 Maurer BT, Stern AG, Kinossian B, Cook KD, Schumacher HR, Jr. Osteoarthritis of the knee:
isokinetic quadriceps exercise versus an educational intervention. Archives of Physical
285 Mazieres B, Bard H, Ligier M, Bru I, Giret d'Orsay G, Le Pen C. Medicoeconomic evaluation of
hyaluronic acid for knee osteoarthritis in everyday practice: the MESSAGE study. Joint, Bone,
Spine: Revue Du Rhumatisme. France 2007; 74(5):453-460
286 Mazieres B, Loyau G, Menkes CJ, Valat JP, Dreiser RL, Charlot J et al. [Chondroitin sulfate in the
treatment of gonarthrosis and coxarthrosis. 5-months result of a multicenter double-blind
controlled prospective study using placebo]. Revue Du Rhumatisme Et Des Maladies Osteo-
Articulaires. 1992; 59(7-8):466-472
287 Mazieres B, Hucher M, Zaim M, Garnero P. Effect of chondroitin sulphate in symptomatic knee
osteoarthritis: a multicentre, randomised, double-blind, placebo-controlled study. Annals of
the Rheumatic Diseases. 2007; 66(5):639-645
288 McAlindon T, Formica M, LaValley M, Lehmer M, Kabbara K. Effectiveness of glucosamine for

symptoms of knee osteoarthritis: results from an internet-based randomized double-blind
controlled trial. American Journal of Medicine. 2004; 117(9):643-649
289 McCaffrey R, Freeman E. Effect of music on chronic osteoarthritis pain in older people. Journal
of Advanced Nursing. 2003; 44(5):517-524
290 McCarthy CJ, Callaghan MJ, Oldham JA. Pulsed electromagnetic energy treatment offers no
clinical benefit in reducing the pain of knee osteoarthritis: a systematic review. BMC
Musculoskeletal Disorders. 2006; 7:51
291 McCarthy CJ, Mills PM, Pullen R, Richardson G, Hawkins N, Roberts CR. Supplementation of a
home-based exercise programme with a class-based programme for people with osteoarthritis
of the knees: a randomised controlled trial and health economic analysis. Health Technology
Assessment. 2004;1
292 McCarthy CJ, Mills PM, Pullen R, Roberts C, Silman A, Oldham JA. Supplementing a home
exercise programme with a class-based exercise programme is more effective than home
exercise alone in the treatment of knee osteoarthritis. Rheumatology. 2004; 43(7):880-886
293 McCleane G. The analgesic efficacy of topical capsaicin is enhanced by glyceryl trinitrate in
painful osteoarthritis: a randomized, double blind, placebo controlled study. European Journal
of Pain. 2000; 4(4):355-360
294 McCrae F, Shouls J, Dieppe P, Watt I. Scintigraphic assessment of osteoarthritis of the knee
joint. Annals of the Rheumatic Diseases. 1992; 51(8):938-942
295 McHugh GA, Campbell M, Luker KA. Quality of care for individuals with osteoarthritis: a
longitudinal study. Journal of Evaluation in Clinical Practice. 2012; 18(3):534-541
296 McHugh GA, Luker KA. Individuals' expectations and challenges following total hip
replacement: a qualitative study. Disability and Rehabilitation. 2012; 34(16):1351-1357
297 McIntyre RL, Irani MS, Piris J. Histological study of the effects of three anti-inflammatory
preparations on the gastric mucosa. Journal of Clinical Pathology. 1981; 34(8):836-842

481
Osteoarthritis
Reference list
298 McKell D, Stewart A. A cost-minimisation analysis comparing topical versus systemic NSAIDs in
the treatment of mild osteoarthritis of the superficial joints. British Journal of Medical
Economics. 1994; 7(2):137-146
299 McKenna F. Celecoxib versus diclofenac in the management of osteoarthritis of the knee.
Scandinavian Journal of Rheumatology. 2001; 30(1):11-18
300 Meding JB, Anderson AR, Faris PM, Keating EM, Ritter MA. Is the preoperative radiograph
useful in predicting the outcome of a total hip replacement? Clinical Orthopaedics and Related
Research. 2000; 376:156-160
301 Meenagh GK, Patton J, Kynes C, Wright GD. A randomised controlled trial of intra-articular
corticosteroid injection of the carpometacarpal joint of the thumb in osteoarthritis. Annals of
the Rheumatic Diseases. 2004; 63(10):1260-1263
302 Merchan ECR, Galindo E. Arthroscope-guided surgery versus nonoperative treatment for
limited degenerative osteoarthritis of the femorotibial joint in patients over 50 years of age: A
prospective comparative study. Arthroscopy. 1993; 9(6):663-667
303 Messieh M. Preoperative risk factors associated with symptomatic pulmonary embolism after
total knee arthroplasty. Orthopedics. 1999; 22(12):1147-1149
304 Messier SP, Loeser RF, Miller GD, Morgan TM, Rejeski WJ, Sevick MA et al. Exercise and dietary
weight loss in overweight and obese older adults with knee osteoarthritis: the Arthritis, Diet,
and Activity Promotion Trial. Arthritis and Rheumatism. 2004; 50(5):1501-1510
305 Messier SP, Mihalko S, Loeser RF, Legault C, Jolla J, Pfruender J et al. Glucosamine/chondroitin
combined with exercise for the treatment of knee osteoarthritis: a preliminary study.
Osteoarthritis and Cartilage. 2007; 15(11):1256-1266
306 Messier SP, Royer TD, Craven TE, O'Toole ML, Burns R, Ettinger WH, Jr. Long-term exercise and
its effect on balance in older, osteoarthritic adults: results from the Fitness, Arthritis, and
Seniors Trial (FAST). Journal of the American Geriatrics Society. 2000; 48(2):131-138
307 Messier SP, Thompson CD, Ettinger WH, Jr. Effects of long-term aerobic or weight training
regimens on gait in an older, osteoarthritic population. Journal of Applied Biomechanics. 1997;
13(2):205-225
308 Micallef M, Nadesapillai S. Evaluation of a widespread bone and joint pain bone scan protocol.
Internal Medicine Journal. 2010; 40:28-29
309 Miceli-Richard C, Le Bars M, Schmidely N, Dougados M. Paracetamol in osteoarthritis of the

knee. Annals of the Rheumatic Diseases. 2004; 63(8):923-930
310 Michel BA, Stucki G, Frey D, De Vathaire F, Vignon E, Bruehlmann P et al. Chondroitins 4 and 6
sulfate in osteoarthritis of the knee: a randomized, controlled trial. Arthritis and Rheumatism.
2005; 52(3):779-786
311 Miller GD, Nicklas BJ, Davis C, Loeser RF, Lenchik L, Messier SP. Intensive weight loss program
improves physical function in older obese adults with knee osteoarthritis. Obesity. 2006;
14(7):1219-1230

482
Osteoarthritis
Reference list
312 Miller GD, Rejeski WJ, Williamson JD, Morgan T, Sevick MA, Loeser RF et al. The Arthritis, Diet
and Activity Promotion Trial (ADAPT): design, rationale, and baseline results. Controlled Clinical
Trials. 2003; 24(4):462-480
313 Minor MA. Exercise in the treatment of osteoarthritis. Rheumatic Diseases Clinics of North
America. 1999; 25(2):397-415, viii
314 Minor MA, Hewett JE, Webel RR, Anderson SK, Kay DR. Efficacy of physical conditioning
exercise in patients with rheumatoid arthritis and osteoarthritis. Arthritis and Rheumatism.
1989; 32(11):1396-1405
315 Mitchell H, Cunningham TJ, Mathews JD, Muirden KD. Further look at dextropropoxyphene
with or without paracetamol in the treatment of arthritis. Medical Journal of Australia. 1984;
140(4):224-225
316 Moller I, Perez M, Monfort J, Benito P, Cuevas J, Perna C et al. Effectiveness of chondroitin
sulphate in patients with concomitant knee osteoarthritis and psoriasis: A randomized, double-
blind, placebo-controlled study. Osteoarthritis and Cartilage. 2010; 18(SUPPL. 1):S32-S40
317 Morreale P, Manopulo R, Galati M, Boccanera L, Saponati G, Bocchi L. Comparison of the

antiinflammatory efficacy of chondroitin sulfate and diclofenac sodium in patients with knee
osteoarthritis. Journal of Rheumatology. 1996; 23(8):1385-1391
318 Moseley JB, O'Malley K, Petersen NJ, Menke TJ, Brody BA, Kuykendall DH et al. A controlled
trial of arthroscopic surgery for osteoarthritis of the knee. New England Journal of Medicine.
2002; 347(2):81-88
319 Moss P, Sluka K, Wright A. The initial effects of knee joint mobilization on osteoarthritic
hyperalgesia. Manual Therapy. 2007; 12(2):109-118
320 Munteanu SE, Zammit GV, Menz HB, Landorf KB, Handley CJ, Elzarka A et al. Effectiveness of
intra-articular hyaluronan (Synvisc, hylan G-F 20) for the treatment of first
metatarsophalangeal joint osteoarthritis: a randomised placebo-controlled trial. Annals of the
321 Murray CJ, Lopez AD. Evidence-based health policy--lessons from the Global Burden of Disease
Study. Science. 1996; 274(5288):740-743
322 National Collaborating Centre for Chronic Conditions. The care and management of
osteoarthritis in adults. London. Royal College of Physicians, 2008. Available from:
http://guidance.nice.org.uk/CG59
323 National Institute for Health and Clinical Excellence. Obesity: the prevention, identification,
assessment and management of overweight and obesity in adults and children. London. NICE,
2006. Available from: www.nice.org.uk
324 National Institute for Health and Clinical Excellence. Depression (amended): management of
depression in primary and secondary care. London. NICE, 2007. Available from:
http://guidance.nice.org.uk
325 National Institute for Health and Clinical Excellence. Guide to the methods of technology
appraisal. London: National Institute for Health and Clinical Excellence; 2008. Available from:
http://www.nice.org.uk/media/B52/A7/TAMethodsGuideUpdatedJune2008.pdf

483
Osteoarthritis
Reference list
326 National Institute for Health and Clinical Excellence. Social value judgements: principles for the
development of NICE guidance. 2nd edition. London: National Institute for Health and Clinical
Excellence; 2008. Available from:
http://www.nice.org.uk/media/C18/30/SVJ2PUBLICATION2008.pdf
327 National Institute for Health and Clinical Excellence. The guidelines manual. London: National
Institute for Health and Clinical Excellence; 2009. Available from:
http://www.nice.org.uk/aboutnice/howwework/developingniceclinicalguidelines/clinicalguidel
inedevelopmentmethods/GuidelinesManual2009.jsp
328 Navarro-Sarabia F, Coronel P, Collantes E, Navarro FJ, de la Serna AR, Naranjo A et al. A 40-
month multicentre, randomised placebo-controlled study to assess the efficacy and carry-over
effect of repeated intra-articular injections of hyaluronic acid in knee osteoarthritis: the
AMELIA project. Annals of the Rheumatic Diseases. 2011; 70(11):1957-1962
329 Naylor CD, Williams JI. Primary hip and knee replacement surgery: Ontario criteria for case
selection and surgical priority. Quality in Health Care. 1996; 5(1):20-30
330 Niethard FU, Gold MS, Solomon GS, Liu JM, Unkauf M, Albrecht HH et al. Efficacy of topical
diclofenac diethylamine gel in osteoarthritis of the knee. Journal of Rheumatology. 2005;
32(12):2384-2392
331 Nigg BM, Emery C, Hiemstra LA. Unstable shoe construction and reduction of pain in
osteoarthritis patients. Medicine & Science in Sports & Exercise. 2006; 38(10):1701-1708
332 Nikles CJ, Yelland M, Glasziou PP, del Mar C. Do individualized medication effectiveness tests
(n-of-1 trials) change clinical decisions about which drugs to use for osteoarthritis and chronic
pain? American Journal of Therapeutics. 2005; 12(1):92-97
333 Nilsdotter AK, Aurell Y, Siosteen AK, Lohmander LS, Roos HP. Radiographic stage of
osteoarthritis or sex of the patient does not predict one year outcome after total hip
arthroplasty. Annals of the Rheumatic Diseases. 2001; 60(3):228-232
334 Nunez M, Nunez E, Segur JM, Macule F, Quinto L, Hernandez MV et al. The effect of an
educational program to improve health-related quality of life in patients with osteoarthritis on
waiting list for total knee replacement: a randomized study. Osteoarthritis and Cartilage. 2006;
14(3):279-285
335 Ones K, Tetik S, Tetik C, Ones N. The effects of heat on osteoarthritis of the knee. Pain Clinic.
2006; 18(1):67-75
336 Organisation for Economic Co-operation and Development (OECD). Purchasing power parities
(PPP). 2012. Available from: http://www.oecd.org/std/ppp [Last accessed: 3 October 2012]
337 Osiri M, Welch V, Brosseau L, Shea B, Mcgowan J, Tugwell P et al. Transcutaneous

electrostimulation for osteoarthritis of the knee. Cochrane Database of Systematic Reviews.
2000; Issue 4:CD002823. DOI:10.1002/14651858.CD002823
338 Ostergaard M, Stoltenberg M, Gideon P, Sorensen K, Henriksen O, Lorenzen I. Changes in

synovial membrane and joint effusion volumes after intraarticular methylprednisolone. Journal
of Rheumatology. 1996; 23:1151-1161

484
Osteoarthritis
Reference list
339 Paker N, Tekdos D, Kesiktas N, Soy D. Comparison of the therapeutic efficacy of TENS versus
intra-articular hyaluronic acid injection in patients with knee osteoarthritis: A prospective
randomized study. Advances in Therapy. 2006; 23(2):342-353
340 Pariser D, O'Hanlon A, Espinoza L. Effects of telephone intervention on arthritis self-efficacy,

depression, pain, and fatigue in older adults with arthritis. Journal of Geriatric Physical
Therapy. 2005; 28(3):67-73
341 Parr G, Darekar B, Fletcher A, Bulpitt CJ. Joint pain and quality of life; results of a randomised
trial. British Journal of Clinical Pharmacology. 1989; 27(2):235-242
342 Patrick DL, Ramsey SD, Spencer AC, Kinne S, Belza B, Topolski TD. Economic evaluation of
aquatic exercise for persons with osteoarthritis. Medical Care. 2001; 39(5):413-424
343 Patru S, Marcu IR, Bighea AC, Popescu R. Efficacy of glucosamine sulfate (GS) in hand
osteoarthritis. Osteoporosis International. 2012; 23:S169
344 Pavelka K, Gatterova J, Olejarova M, Machacek S, Giacovelli G, Rovati LC. Glucosamine sulfate
use and delay of progression of knee osteoarthritis: a 3-year, randomized, placebo-controlled,
double-blind study. Archives of Internal Medicine. 2002; 162(18):2113-2123
345 Pavelka K, Manopulo R, Busci L. Double-blind, dose-effect study of oral chondroitin 4 & 6
sulfate 1200 mg, 800 mg, 200 mg, and placebo in the treatment of knee osteoarthritis. Litera
Rheumatologica. 1999; 24:21-30
346 Pavelka K, Uebelhart D. Efficacy evaluation of highly purified intra-articular hyaluronic acid
(Sinovial([R])) vs hylan G-F20 (Synvisc([R])) in the treatment of symptomatic knee
osteoarthritis. A double-blind, controlled, randomized, parallel-group non-inferiority study.
347 Peacock M, Rapier C. The topical NSAID felbinac is a cost effective alternative to oral NSAIDs for
the treatment of rheumatic conditions. British Journal of Medical Economics. 1993; 6:135-142
348 Peat G, McCarney R, Croft P. Knee pain and osteoarthritis in older adults: a review of
community burden and current use of primary health care. Annals of the Rheumatic Diseases.
2001; 60(2):91-97
349 Peat G, Thomas E, Duncan R, Wood L, Hay E, Croft P. Clinical classification criteria for knee
osteoarthritis: performance in the general population and primary care. Annals of the
350 Peloquin L, Bravo G, Gauthier P, Lacombe G, Billiard JS. Effects of a cross-training exercise
program in persons with osteoarthritis of the knee. A randomized controlled trial. Journal of
Clinical Rheumatology. 1999; 5(3):126-136
351 Penninx BW, Messier SP, Rejeski WJ, Williamson JD, DiBari M, Cavazzini C et al. Physical
exercise and the prevention of disability in activities of daily living in older persons with
osteoarthritis. Archives of Internal Medicine. 2001; 161(19):2309-2316
352 Penninx BW, Rejeski WJ, Pandya J, Miller ME, Di Bari M, Applegate WB et al. Exercise and
depressive symptoms: a comparison of aerobic and resistance exercise effects on emotional
and physical function in older persons with high and low depressive symptomatology. Journals
of Gerontology Series B-Psychological Sciences & Social Sciences. 2002; 57(2):124-132

485
Osteoarthritis
Reference list
353 Perlman AI, Sabina A, Williams AL, Njike VY, Katz DL. Massage therapy for osteoarthritis of the
knee: a randomized controlled trial. Archives of Internal Medicine. 2006; 166(22):2533-2538
354 Perpignano G. Double-blind comparison of the efficacy and safety of etodolac SR 600 mg u.i.d.
and of tenoxicam 20 mg u.i.d. in elderly patients with osteoarthritis of the hip and of the knee.
International Journal of Clinical Pharmacology Research. 1994; 14(5-6):203-216
355 Peters TJ, Sanders C, Dieppe P, Donovan J. Factors associated with change in pain and disability
over time: a community-based prospective observational study of hip and knee osteoarthritis.
British Journal of General Practice. 2005; 55(512):205-211
356 Petrella RJ, Decaria J, Petrella MJ. Long term efficacy and safety of a combined low and high
molecular weight hyaluronic acid in the treatment of osteoarthritis of the knee. Rheumatology
Reports. 2011; 3(1):16-21
357 Petrella RJ, Petrella M. A prospective, randomized, double-blind, placebo controlled study to
evaluate the efficacy of intraarticular hyaluronic acid for osteoarthritis of the knee. Journal of
Rheumatology. 2006; 33(5):951-956
358 Petron DJ, Greis PE, Aoki SK, Black S, Krete D, Sohagia KB et al. Use of knee magnetic resonance
imaging by primary care physicians in patients aged 40 years and older. Sports Health. 2010;
2(5):385-390
359 Pham T, Maillefert JF, Hudry C, Kieffert P, Bourgeois P, Lechevalier D et al. Laterally elevated
wedged insoles in the treatment of medial knee osteoarthritis. A two-year prospective
randomized controlled study. Osteoarthritis and Cartilage. 2004; 12(1):46-55
360 Pham T, van der Heijde D, Lassere M, Altman RD, Anderson JJ, Bellamy N et al. Outcome
variables for osteoarthritis clinical trials: The OMERACT-OARSI set of responder criteria. Journal
of Rheumatology. 2003; 30(7):1648-1654
361 Pincus T. Patient Preference for Placebo, Acetaminophen (paracetamol) or Celecoxib Efficacy
Studies (PACES): two randomised, double blind, placebo controlled, crossover clinical trials in
patients with knee or hip osteoarthritis. Annals of the Rheumatic Diseases. 2004; 63(8):931-
939
362 Pipitone N, Scott DL. Magnetic pulse treatment for knee osteoarthritis: a randomised, double-
blind, placebo-controlled study. Current Medical Research and Opinion. 2001; 17(3):190-196
363 Pisters MF, Veenhof C, Van Meeteren NLU, Ostelo RW, De Barker DH, Schellevis FG et al. Long-
term effectiveness of exercise therapy in patients with osteoarthritis of the hip or knee: A
systematic review. Arthritis Care and Research. 2007; 57(7):1245-1253
364 Pons M, Alvarez F, Solana J, Viladot R, Varela L. Sodium hyaluronate in the treatment of hallux
rigidus. A single-blind, randomized study. Foot and Ankle International. 2007; 28(1):38-42
365 Pujalte JM, Llavore EP, Ylescupidez FR. Double-blind clinical evaluation of oral glucosamine
sulphate in the basic treatment of osteoarthrosis. Current Medical Research and Opinion.
1980; 7(2):110-114
366 Quilty B, Tucker M, Campbell R, Dieppe P. Physiotherapy, including quadriceps exercises and
patellar taping, for knee osteoarthritis with predominant patello-femoral joint involvement:
randomized controlled trial. Journal of Rheumatology. 2003; 30(6):1311-1317

486
Osteoarthritis
Reference list
367 Quintana JM, Arostegui I, Azkarate J, Goenaga JI, Elexpe X, Letona J et al. Evaluation of explicit
criteria for total hip joint replacement. Journal of Clinical Epidemiology. 2000; 53(12):1200-
1208
368 Qvistgaard E, Christensen R, Torp-Pedersen S, Bliddal H. Intra-articular treatment of hip

osteoarthritis: A randomized trial of hyaluronic acid, corticosteroid, and isotonic saline.
369 Rai J, Pal SK, Gul A, Senthil R, Singh H. Efficacy of chondroitin sulfate and glucosamine sulfate in
the progression of symptomatic knee osteoarthritis: A randomized, placebo-controlled, double
blind study. Bulletin of the Postgraduate Institute of Medical Education and Research. 2004;
38(1):18-22
370 Railhac JJ, Zaim M, Saurel AS, Vial J, Fournie B. Effect of 12months treatment with chondroitin
sulfate on cartilage volume in knee osteoarthritis patients: a randomized, double-blind,
placebo-controlled pilot study using MRI. Clinical Rheumatology. 2012; 31(9):1347-1357
371 Ramos-Remus C, Salcedo-Rocha AL, Prieto-Parra RE, Galvan-Villegas F. How important is

patient education? Baillieres Best Practice in Clinical Rheumatology. 2000; 14(4):689-703
372 Ravaud P, Flipo RM, Boutron I, Roy C, Mahmoudi A, Giraudeau B et al. ARTIST (osteoarthritis
intervention standardized) study of standardised consultation versus usual care for patients
with osteoarthritis of the knee in primary care in France: pragmatic randomised controlled
trial. BMJ. 2009; 338:b421
373 Ravaud P, Moulinier L, Giraudeau B, Ayral X, Guerin C, Noel E et al. Effects of joint lavage and
steroid injection in patients with osteoarthritis of the knee: results of a multicenter,
randomized, controlled trial. Arthritis and Rheumatism. 1999; 42(3):475-482
374 Raynauld JP, Torrance GW, Band PA, Goldsmith CH, Tugwell P, Walker V et al. A prospective,
randomized, pragmatic, health outcomes trial evaluating the incorporation of hylan G-F 20 into
the treatment paradigm for patients with knee osteoarthritis (Part 1 of 2): clinical results.
375 Reginster JY, Deroisy R, Rovati LC, Lee RL, Lejeune E, Bruyere O et al. Long-term effects of
glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical
trial. Lancet. 2001; 357(9252):251-256
376 Reichenbach S, Sterchi R, Scherer M, Trelle S, Burgi E, Burgi U et al. Meta-analysis: chondroitin
for osteoarthritis of the knee or hip. Annals of Internal Medicine. 2007; 146(8):580-590
377 Reinhold T, Witt CM, Jena S, Brinkhaus B, Willich SN. Quality of life and cost-effectiveness of
acupuncture treatment in patients with osteoarthritis pain. European Journal of Health
Economics. 2008; 9(3):209-219
378 Rejeski WJ, Craven T, Ettinger WH, Jr., McFarlane M, Shumaker S. Self-efficacy and pain in
disability with osteoarthritis of the knee. Journals of Gerontology Series B-Psychological
Sciences & Social Sciences. 1996; 51(1):24-29
379 Rejeski WJ, Focht BC, Messier SP, Morgan T, Pahor M, Penninx B. Obese, older adults with knee
osteoarthritis: weight loss, exercise, and quality of life. Health Psychology. 2002; 21(5):419-426

487
Osteoarthritis
Reference list
380 Rejeski WJ, Martin KA, Miller ME, Ettinger WH, Jr., Rapp S. Perceived importance and
satisfaction with physical function in patients with knee osteoarthritis. Annals of Behavioral
Medicine. 1998; 20(2):141-148
381 Revicki D, Hays RD, Cella D, Sloan J. Recommended methods for determining responsiveness
and minimally important differences for patient-reported outcomes. Journal of Clinical
Epidemiology. 2008; 61(2):102-109
382 Richards JD. A comparison of knee braces during walking for the treatment of osteoarthritis of
the medial compartment of the knee. Journal of Bone and Joint Surgery - British Volume. 2005;
87(7):937-939
383 Richette P, Ravaud P, Conrozier T, Euller-Ziegler L, MaziŠres B, Maugars Y et al. Effect of

hyaluronic acid in symptomatic hip osteoarthritis: a multicenter, randomized, placebo-
controlled trial. Arthritis and Rheumatism. 2009; 60(3):824-830
384 Robinson VA, Brosseau L, Peterson J. Therapeutic ultrasound for osteoarthritis of the knee.
Cochrane Database of Systematic Reviews. 2001; Issue 3:CD003132.
DOI:10.1002/14651858.CD003132
385 Roddy E, Zhang W, Doherty M. Aerobic walking or strengthening exercise for osteoarthritis of
the knee? A systematic review. Annals of the Rheumatic Diseases. 2005; 64(4):544-548
386 Roder C, Staub LP, Eggli S, Dietrich D, Busato A, Muller U. Influence of preoperative functional
status on outcome after total hip arthroplasty. Journal of Bone and Joint Surgery - American
Volume. 2007; 89(1):11-17
387 Rogind H. Comparison of etodolac and piroxicam in patients with osteoarthritis of the hip or
knee: A prospective, randomised, double-blind, controlled multicentre study. Clinical Drug
Investigation. 1997; 13(2):66-75
388 Rolf C, Engstrom B, Beauchard C, Jacobs LD, Le LA. Intra-articular absorption and distribution of
ketoprofen after topical plaster application and oral intake in 100 patients undergoing knee
arthroscopy. Rheumatology. 1999; 38(6):564-567
389 Rosemann T, Joos S, Laux G, Gensichen J, Szecsenyi J. Case management of arthritis patients in
primary care: a cluster-randomized controlled trial. Arthritis and Rheumatism. 2007;
57(8):1390-1397
390 Rothacker D, Difigilo C, Lee I. A clinical trial of topical 10% trolamine salicylate in osteoarthritis.
Current Therapeutic Research - Clinical and Experimental. 1994; 55(5):584-597
391 Rothacker D, Lee I, Littlejohn III TW. Effectiveness of a single topical application of 10%
trolamine salicylate cream in the symptomatic treatment of osteoarthritis. Journal of Clinical
Rheumatology. 1998; 4(1):6-12
392 Rovati LC. The clinical profile of glucosamine sulfate as a selective symptom-modifying drug in
osteoarthritis: current data and perspectives. Osteoarthritis and Cartilage. 1997; 5:72
393 Rovetta G. Galactosaminoglycuronoglycan sulfate (matrix) in therapy of tibiofibular

osteoarthritis of the knee. Drugs Under Experimental and Clinical Research. 1991; 17(1):53-57
394 Sadr AO, Bellocco R, Eriksson K, Adami J. The impact of tobacco use and body mass index on
the length of stay in hospital and the risk of post-operative complications among patients

488
Osteoarthritis
Reference list
undergoing total hip replacement. Journal of Bone and Joint Surgery - British Volume. 2006;
88(10):1316-1320
395 Salaffi F, Cavalieri F, Nolli M, Ferraccioli G. Analysis of disability in knee osteoarthritis.

Relationship with age and psychological variables but not with radiographic score. Journal of
Rheumatology. 1991; 18(10):1581-1586
396 Salk RS, Chang TJ, D'Costa WF, Soomekh DJ, Grogan KA. Sodium hyaluronate in the treatment
of osteoarthritis of the ankle: A controlled, randomized, double-blind pilot study. Journal of
Bone and Joint Surgery - American Volume. 2006; 88(2):295-302
397 Sanda M, Collins SH, Mahady J. Three-month multicenter study of etodolac (Ultradol(TM)) in
patients with osteoarthritis of the hip. Current Therapeutic Research - Clinical and
Experimental. 1983; 33(5):782-792
398 Sanders C, Donovan J, Dieppe P. The significance and consequences of having painful and
disabled joints in older age: co-existing accounts of normal and disrupted biographies.
Sociology of Health and Illness. 2002; 24(2):227-253
399 Sanders C, Donovan JL, Dieppe PA. Unmet need for joint replacement: a qualitative
investigation of barriers to treatment among individuals with severe pain and disability of the
hip and knee. Rheumatology. 2004; 43(3):353-357
400 Sangdee C, Teekachunhatean S, Sananpanich K, Sugandhavesa N, Chiewchantanakit S,

Pojchamarnwiputh S et al. Electroacupuncture versus diclofenac in symptomatic treatment of
osteoarthritis of the knee: a randomized controlled trial. BMC Complementary and Alternative
Medicine. 2002; 2:3
401 Sawitzke AD, Shi H, Finco MF, Dunlop DD, Bingham CO, Harris CL et al. The effect of
glucosamine and/or chondroitin sulfate on the progression of knee osteoarthritis: a report
from the glucosamine/chondroitin arthritis intervention trial. Arthritis and Rheumatism. 2008;
58(10):3183-3191
402 Sawitzke AD, Shi H, Finco MF, Dunlop DD, Harris CL, Singer NG et al. Clinical efficacy and safety
of glucosamine, chondroitin sulphate, their combination, celecoxib or placebo taken to treat
osteoarthritis of the knee: 2-year results from GAIT. Annals of the Rheumatic Diseases. 2010;
69(8):1459-1464
403 Schaefer M, DeLattre M, Gao X, Stephens J, Botteman M, Morreale A. Assessing the cost-
effectiveness of COX-2 specific inhibitors for arthritis in the Veterans Health Administration.
404 Scharf HP, Mansmann U, Streitberger K, Witte S, Kramer J, Maier C et al. Acupuncture and knee
osteoarthritis: a three-armed randomized trial. Annals of Internal Medicine. 2006; 145(1):12-20
405 Scheiman JM, Yeomans ND, Talley NJ, Vakil N, Chan FK, Tulassay Z et al. Prevention of ulcers by
esomeprazole in at-risk patients using non-selective NSAIDs and COX-2 inhibitors. American
Journal of Gastroenterology. 2006; 101(4):701-710
406 Schiphof D, de Klerk BM, Koes BW, Bierma-Zeinstra S. Good reliability, questionable validity of
25 different classification criteria of knee osteoarthritis: a systematic appraisal. Journal of
Clinical Epidemiology. 2008; 61(12):1205-1215

489
Osteoarthritis
Reference list
407 Schmalzried TP, Silva M, de la Rosa MA, Choi ES, Fowble VA. Optimizing patient selection and
outcomes with total hip resurfacing. Clinical Orthopaedics and Related Research. 2005;
441:200-204
408 Schnitzer TJ, Burmester GR, Mysler E. Comparison of lumiracoxib with naproxen and ibuprofen
in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in
ulcer complications: randomised controlled trial. Lancet. 2004; 364(9435):665-674
409 Schnitzer TJ, Morton C, Coker S. Topical capsaicin therapy for osteoarthritis pain: Achieving a
maintenance regimen. Seminars in Arthritis and Rheumatism. 1994; 23(suppl 3):34-40
410 Scholtissen S, Bruyere O, Neuprez A, Severens JL, Herrero-Beaumont G, Rovati L et al.

Glucosamine sulphate in the treatment of knee osteoarthritis: cost-effectiveness comparison
with paracetamol. International Journal of Clinical Practice. 2010; 64(6):756-762
411 Scott S. Shortwave diathermy. In: Kitchen S, Bazin S (eds), Clayton's electrotherapy 10E,
London: WB Saunders Company Limited, 1996: 154-178
412 Scott WA. The relief of pain with an antidepressant in arthritis. Practitioner. 1969;
202(212):802-807
413 Segal L, Day SE, Chapman AB, Osborne RH. Can we reduce disease burden from osteoarthritis?
Medical Journal of Australia. 2004; 180(5 suppl):1-7
414 Sevick MA, Bradham DD, Muender M, Chen GJ, Enarson C, Dailey M et al. Cost-effectiveness of
aerobic and resistance exercise in seniors with knee osteoarthritis. Medicine & Science in
Sports & Exercise. 2000; 32(9):1534-1540
415 Shackel NA, Day RO, Kellett B, Brooks PM. Copper-salicylate gel for pain relief in osteoarthritis:
a randomised controlled trial. Medical Journal of Australia. 1997; 167(3):134-136
416 Sheldon EB. Efficacy and tolerability of lumiracoxib in the treatment of osteoarthritis of the
knee: a 13-week, randomized, double-blind comparison with celecoxib and placebo. Clinical
Therapeutics. 2005; 27(1):64-77
417 Shimizu M, Higuchi H, Takagishi K, Shinozaki T, Kobayashi T. Clinical and biochemical

characteristics after intra-articular injection for the treatment of osteoarthritis of the knee:
Prospective randomized study of sodium hyaluronate and corticosteroid. Journal of
Orthopaedic Science. 2010; 15(1):51-56
418 Singh G, Fort JG, Goldstein JL, Levy RA, Hanrahan PS, Bello AE et al. Celecoxib versus naproxen
and diclofenac in osteoarthritis patients: SUCCESS-I Study. American Journal of Medicine. 2006;
119(3):255-266
419 Skwara A, Peterlein CD, Tibesku CO, Rosenbaum D, Fuchs-Winkelmann S. Changes of gait
patterns and muscle activity after intraarticular treatment of patients with osteoarthritis of the
knee: a prospective, randomised, doubleblind study. Knee. 2009; 16(6):466-472
420 Skwara A, Ponelis R, Tibesku CO, Rosenbaum D, Fuchs-Winkelmann S. Gait patterns after
intraarticular treatment of patients with osteoarthritis of the knee--hyaluronan versus
triamcinolone: a prospective, randomized, doubleblind, monocentric study. European Journal
of Medical Research. 2009; 14(4):157-164

490
Osteoarthritis
Reference list
421 Smugar SS, Schnitzer TJ, Weaver AL. Rofecoxib 12.5 mg, rofecoxib 25 mg, and celecoxib 200 mg
in the treatment of symptomatic osteoarthritis: results of two similarly designed studies.
422 Sobel DS. Rethinking medicine: improving health outcomes with cost-effective psychosocial
interventions. Psychosomatic Medicine. 1995; 57(3):234-244
423 Solomon DH, Chibnik LB, Losina E, Huang J, Fossel AH, Husni E et al. Development of a
preliminary index that predicts adverse events after total knee replacement. Arthritis and
Rheumatism. 2006; 54(5):1536-1542
424 Soroka NF, Chyzh KA. Clinical efficiency and pharmacoeconomical evaluation of treatment by
chondroitinsulphate (Structumc) in patients with primary osteoarthritis (POA). Annals of the
Rheumatic Diseases. 2002; 61(Suppl 1):AB0289
425 Sowers JR, White WB. The Effects of cyclooxygenase-2 inhibitors and nonsteroidal anti-
inflammatory therapy on 24-hour blood pressure in patients with hypertension, osteoarthritis,
and type 2 diabetes mellitus. Archives of Internal Medicine. 2005; 165(2):161-168
426 Spicer DD, Pomeroy DL, Badenhausen WE, Schaper LAJ, Curry JI, Suthers KE et al. Body mass
index as a predictor of outcome in total knee replacement. International Orthopaedics. 2001;
25(4):246-249
427 Spiegel BM, Targownik L, Dulai GS, Gralnek IM. The cost-effectiveness of cyclooxygenase-2
selective inhibitors in the management of chronic arthritis. Annals of Internal Medicine. 2003;
138(10):795-806
428 Spitzer AI, Bockow BI, Brander VA, Yates JW, MacCarter DK, Gudger GK et al. Hylan G-F 20
improves hip osteoarthritis: a prospective, randomized study. Physician and Sportsmedicine.
2010; 38(2):35-47
429 Stacey D, Bennett CL, Barry MJ, Col NF, Eden KB, Holmes-Rovner M et al. Decision aids for
people facing health treatment or screening decisions. Cochrane Database of Systematic
Reviews. 2011; Issue 10:CD001431. DOI:10.1002/14651858.CD001431.pub3
430 Stamm TA, Machold KP, Smolen JS. Joint protection and home hand exercises improve hand
function in patients with hand osteoarthritis: a randomized controlled trial. Arthritis and
Rheumatism. 2002; 47(1):44-49
431 Stewart M, Brown JB, Weston WW. Patient-centered medicine:transforming the clinical
method. 2nd edition. USA: Radcliffe Medical Press; 2003
432 Suarez-Almazor ME, Looney C, Liu Y, Cox V, Pietz K, Marcus DM et al. A randomized controlled
trial of acupuncture for osteoarthritis of the knee: effects of patient-provider communication.
Arthritis Care and Research. 2010; 62(9):1229-1236
433 Suarez-Almazor ME, Richardson M, Kroll TL, Sharf BF. A qualitative analysis of decision-making
for total knee replacement in patients with osteoarthritis. Journal of Clinical Rheumatology.
2010; 16(4):158-163
434 Suarez-Otero R. Efficacy and safety of diclofenac-cholestyramine and celecoxib in

osteoarthritis. Proceedings of the Western Pharmacology Society. 2002; 45:26-28

491
Osteoarthritis
Reference list
435 Superio-Cabuslay E, Ward MM, Lorig KR. Patient education interventions in osteoarthritis and
rheumatoid arthritis: a meta-analytic comparison with nonsteroidal antiinflammatory drug
treatment. Arthritis Care and Research. 1996; 9(4):292-301
436 Sutton D, Gignac MAM, Cott C. Medical and everyday assistive device use among older adults
with arthritis. Canadian Journal on Aging. 2002; 21(4):535-548
437 Tak ES. The effects of an exercise program for older adults with osteoarthritis of the hip.
438 Tak SH, Laffrey SC. Life satisfaction and its correlates in older women with osteoarthritis.
Orthopaedic Nursing. 2003; 22(3):182-189
439 Takeda W, Wessel J. Acupuncture for the treatment of pain of osteoarthritic knees. Arthritis
Care and Research. 1994; 7(3):118-122
440 Tallon D, Chard J, Dieppe P. Exploring the priorities of patients with osteoarthritis of the knee.
Arthritis Care and Research. 2000; 13(5):312-319
441 Tannenbaum H, Berenbaum F, Reginster JY, Zacher J, Robinson J, Poor G et al. Lumiracoxib is
effective in the treatment of osteoarthritis of the knee: a 13 week, randomised, double blind
study versus placebo and celecoxib. Annals of the Rheumatic Diseases. 2004; 63(11):1419-1426
442 Tascioglu F, Armagan O, Tabak Y, Corapci I, Oner C. Low power laser treatment in patients with
knee osteoarthritis. Swiss Medical Weekly. 2004; 134(17-18):254-258
443 Tavakoli M. Modelling therapeutic strategies in the treatment of osteoarthritis: An economic

evaluation of meloxicam versus diclofenac and piroxicam. Pharmacoeconomics. 2003;
21(6):443-454
444 Temple AR, Benson GD, Zinsenheim JR, Schweinle JE. Multicenter, randomized, double-blind,
active-controlled, parallel-group trial of the long-term (6-12 months) safety of acetaminophen
in adult patients with osteoarthritis. Clinical Therapeutics. 2006; 28(2):222-235
445 ter Haar G. Therapeutic ultrasound. European Journal of Ultrasound. 1999; 9:3-9
446 Thamsborg G, Florescu A, Oturai P, Fallentin E, Tritsaris K, Dissing S. Treatment of knee

osteoarthritis with pulsed electromagnetic fields: a randomized, double-blind, placebo-
controlled study. Osteoarthritis and Cartilage. 2005; 13(7):575-581
447 Thomas KS, Miller P, Doherty M, Muir KR, Jones AC, O'Reilly SC. Cost effectiveness of a two-
year home exercise program for the treatment of knee pain. Arthritis and Rheumatism. 2005;
53(3):388-394
448 Thorstensson CA, Roos EM, Petersson IF, Ekdahl C. Six-week high-intensity exercise program
for middle-aged patients with knee osteoarthritis: a randomized controlled trial. BMC
Musculoskeletal Disorders. 2005; 6(27)
449 Tikiz C, Unlu Z, Sener A, Efe M, Tuzun C. Comparison of the efficacy of lower and higher
molecular weight viscosupplementation in the treatment of hip osteoarthritis. Clinical
Rheumatology. 2005; 24(3):244-250

492
Osteoarthritis
Reference list
450 Toda Y. The effect of energy restriction, walking, and exercise on lower extremity lean body
mass in obese women with osteoarthritis of the knee. Journal of Orthopaedic Science. 2001;
6(2):148-154
451 Toda Y, Tsukimura N. A comparative study on the effect of the insole materials with subtalar
strapping in patients with medial compartment osteoarthritis of the knee. Modern
Rheumatology. 2004; 14(6):459-465
452 Toda Y, Tsukimura N. A six-month followup of a randomized trial comparing the efficacy of a
lateral-wedge insole with subtalar strapping and an in-shoe lateral-wedge insole in patients
with varus deformity osteoarthritis of the knee. Arthritis and Rheumatism. 2004; 50(10):3129-
3136
453 Toda Y, Tsukimura N. A 2-year follow-up of a study to compare the efficacy of lateral wedged
insoles with subtalar strapping and in-shoe lateral wedged insoles in patients with varus
deformity osteoarthritis of the knee. Osteoarthritis and Cartilage. 2006; 14(3):231-237
454 Toda Y, Tsukimura N, Kato A. The effects of different elevations of laterally wedged insoles with
subtalar strapping on medial compartment osteoarthritis of the knee. Archives of Physical
455 Toda Y, Tsukimura N, Segal N. An optimal duration of daily wear for an insole with subtalar
strapping in patients with varus deformity osteoarthritis of the knee. Osteoarthritis and
Cartilage. 2005; 13(4):353-360
456 Torrance GW, Raynauld JP, Walker V, Goldsmith CH, Bellamy N, Band PA et al. A prospective,
randomized, pragmatic, health outcomes trial evaluating the incorporation of hylan G-F 20 into
the treatment paradigm for patients with knee osteoarthritis (Part 2 of 2): economic results.
457 Towheed T, Hochberg MC, Shea B, Wells GA. Analgesia and non-aspirin, non-steroidal anti-
inflammatory drugs for osteoarthritis of the hip. Cochrane Database of Systematic Reviews.
2006; Issue 1:CD000517. DOI:10.1002/14651858.CD000517.pub2
458 Towheed T, Maxwell L, Anastassiades TP, Shea B, Houpt JB, Welch V et al. Glucosamine therapy
for treating osteoarthritis. Cochrane Database of Systematic Reviews. 2005; Issue 2:CD002946.
DOI:10.1002/14651858.CD002946.pub2
459 Towheed T, Maxwell L, Judd M, Catton M, Hochberg MC, Wells GA. Acetaminophen for
DOI:10.1002/14651858.CD004257.pub2
460 Trnavsky K, Fischer M, Vogtle JU, Schreyger F. Efficacy and safety of 5% ibuprofen cream
treatment in knee osteoarthritis. Results of a randomized, double-blind, placebo-controlled
study. Journal of Rheumatology. 2004; 31(3):565-572
461 Tubach F, Dougados M, Falissard B, Baron G, Logeart I, Ravaud P. Feeling good rather than
feeling better matters more to patients. Arthritis and Rheumatism. 2006; 55(4):526-530
462 Tubach F, Ravaud P, Baron G, Falissard B, Logeart I, Bellamy N et al. Evaluation of clinically
relevant changes in patient reported outcomes in knee and hip osteoarthritis: the minimal
clinically important improvement. Annals of the Rheumatic Diseases. 2005; 64(1):29-33

493
Osteoarthritis
Reference list
463 Tucker M, Brantingham JW, Myburg C. Relative effectiveness of a non-steroidal anti-

inflammatory medication (Meloxicam) versus manipulation in the treatment of osteo-arthritis
of the knee. European Journal of Chiropractic. 2003; 50(3):163-183
464 Tuzun EH, Aytar A, Eker L, Daskapan A. Effectiveness of two different physical therapy
programmes in the treatment of knee osteoarthritis. Pain Clinic. 2004; 16(4):379-387
465 Uebelhart D, Thonar EJ, Delmas PD, Chantraine A, Vignon E. Effects of oral chondroitin sulfate
on the progression of knee osteoarthritis: a pilot study. Osteoarthritis and Cartilage. 1998; 6
Suppl A:39-46
466 Urwin M, Symmons D, Allison T, Brammah T, Busby H, Roxby M et al. Estimating the burden of
musculoskeletal disorders in the community: the comparative prevalence of symptoms at
different anatomical sites, and the relation to social deprivation. Annals of the Rheumatic
Diseases. 1998; 57(11):649-655
467 Vaile JH, Davis P. Topical NSAIDs for musculoskeletal conditions. A review of the literature.
Drugs. 1998; 56(5):783-799
468 van Baar ME, Dekker J, Oostendorp RA, Bijl D, Voorn TB, Bijlsma JW. Effectiveness of exercise in
patients with osteoarthritis of hip or knee: nine months' follow up. Annals of the Rheumatic
Diseases. 2001; 60(12):1123-1130
469 van Baar ME, Dekker J, Oostendorp RA, Bijl D, Voorn TB, Lemmens JA et al. The effectiveness of
exercise therapy in patients with osteoarthritis of the hip or knee: a randomized clinical trial.
470 van der Esch M, Heijmans M, Dekker J. Factors contributing to possession and use of walking
aids among persons with rheumatoid arthritis and osteoarthritis. Arthritis and Rheumatism.
2003; 49(6):838-842
471 Vas J, Mendez C, Perea-Milla E, Vega E, Panadero MD, Leon JM et al. Acupuncture as a
complementary therapy to the pharmacological treatment of osteoarthritis of the knee:
randomised controlled trial. BMJ. 2004; 329(7476):1216-1219
472 Veitiene D, Tamulaitiene M. Comparison of self-management methods for osteoarthritis and

rheumatoid arthritis. Journal of Rehabilitation Medicine. 2005; 37(1):58-60
473 Ververeli PA, Sutton DC, Hearn SL, Booth Jr RE, Hozack WJ, Rothman RR. Continuous passive
motion after total knee arthroplasty: Analysis of cost and benefits. Clinical Orthopaedics and
Related Research. 1995;208-215
474 Vickers A, Cronin A, Maschino A, Lewith G, MacPherson H, Victor N et al. Acupuncture for
chronic pain: An individual patient data meta-analysis of randomized trials. BMC
Complementary and Alternative Medicine. 2012; 12
475 Victor CR, Ross F, Axford J. Capturing lay perspectives in a randomized control trial of a health
promotion intervention for people with osteoarthritis of the knee. Journal of Evaluation in
Clinical Practice. 2004; 10(1):63-70
476 Victor CR, Triggs ER. Lack of benefit of a primary care-based nurse-led education programme
for people with osteoarthritis of the knee. Clinical Rheumatology. 2005; 24(4):358-364

494
Osteoarthritis
Reference list
477 Viney RC, King MT, Savage EJ, Hall JP. Use of the TTU is questionable. Medical Journal of
Australia. 2004; 181(6):338-339
478 Waddell D, Rein A, Panarites C, Coleman PM, Weiss C. Cost implications of introducing an
alternative treatment for patients with osteoarthritis of the knee in a managed care setting.
American Journal of Managed Care. 2001; 7(10):981-991
479 Wajon A, Ada L. No difference between two splint and exercise regimens for people with
osteoarthritis of the thumb: a randomised controlled trial. Australian Journal of Physiotherapy.
2005; 51(4):245-249
480 Walsh D. TENS Clinical applications and related theory. New York: Churchill Livingstone; 1997
481 Wandel S, Juni P, Tendal B, Nuesch E, Villiger PM, Welton NJ et al. Effects of glucosamine,
chondroitin, or placebo in patients with osteoarthritis of hip or knee: network meta-analysis.
BMJ. 2010; 341:c4675
482 Wang T, Belza B, Elaine TF, Whitney JD, Bennett K. Effects of aquatic exercise on flexibility,
strength and aerobic fitness in adults with osteoarthritis of the hip or knee. Journal of
Advanced Nursing. 2007; 57(2):141-152
483 Wegman AC, van der Windt DA, de Haanm M, Deville WL, Fo CT, de Vries TP. Switching from
NSAIDs to paracetamol: a series of n of 1 trials for individual patients with osteoarthritis.
484 Weinberger M, Tierney WM, Booher P. Common problems experienced by adults with
485 Weiss S, LaStayo P, Mills A, Bramlet D. Prospective analysis of splinting the first
carpometacarpal joint: an objective, subjective, and radiographic assessment. Journal of Hand
Therapy. 2000; 13(3):218-226
486 Weiss S, LaStayo P, Mills A, Bramlet D. Splinting the degenerative basal joint: custom-made or
prefabricated neoprene? Journal of Hand Therapy. 2004; 17(4):401-406
487 Wetzels R, van Weel C, Grol R, Wensing M. Family practice nurses supporting self-management
in older patients with mild osteoarthritis: a randomized trial. BMC Family Practice. 2008; 9:7
488 Whitehurst DGT, Bryan S, Hay EM, Thomas E, Young J, Foster NE. Cost-effectiveness of
acupuncture care as an adjunct to exercise-based physical therapy for osteoarthritis of the
knee. Physical Therapy. 2011; 91(5):630-641
489 Wielandt T, McKenna K, Tooth L, Strong J. Factors that predict the post-discharge use of
recommended assistive technology (AT). Disability and Rehabilitation: Assistive Technology.
2006; 1(1-2):29-40
490 Wiesenhutter CW, Boice JA. Evaluation of the comparative efficacy of etoricoxib and ibuprofen
for treatment of patients with osteoarthritis: A randomized, double-blind, placebo-controlled
trial. Mayo Clinic Proceedings. 2005; 80(4):470-479
491 Wilder FV, Barrett JP, Farina EJ. Joint-specific prevalence of osteoarthritis of the hand.

495
Osteoarthritis
Reference list
492 Wildi L, Raynauld JP, Martel-Pelletier J, Beaulieu A, Bessette L, Morin F et al. Chondroitin
sulfate reduces both cartilage volume loss and bone marrow lesions in knee OA patients
starting as early as 6 months after initiation of therapy: A randomized, double-blind placebo
controlled pilot study using MRI. Osteoporosis International. 2011; 22:S137
493 Wilkie R, Peat G, Thomas E, Croft P. Factors associated with restricted mobility outside the
home in community-dwelling adults ages fifty years and older with knee pain: an example of
use of the International Classification of Functioning to investigate participation restriction.
494 Wilkie R, Peat G, Thomas E, Croft PR. The potential determinants of restricted mobility outside
the home in community-dwelling older adults with knee pain. 2006;
495 Williams GW, Ettlinger RE, Ruderman EM, Hubbard RC, Lonien ME, Yu SSZ. Treatment of
osteoarthritis with a once-daily dosing regimen of celecoxib: A randomized, controlled trial.
Journal of Clinical Rheumatology. 2000; 6(2):65-74
496 Williams GW, Hubbard RC, Yu SS, Zhao W, Geis GS. Comparison of once-daily and twice-daily
administration of celecoxib for the treatment of osteoarthritis of the knee. Clinical
Therapeutics. 2001; 23(2):213-227
497 Williams PI, Hosie J, Scott JL. Etodolac therapy for osteoarthritis: a double-blind, placebo-
controlled trial. Current Medical Research and Opinion. 1989; 11(7):463-470
498 Witt C, Brinkhaus B, Jena S, Linde K, Streng A, Wagenpfeil S et al. Acupuncture in patients with
osteoarthritis of the knee: a randomised trial. Lancet. 2005; 366(9480):136-143
499 Witt CM, Brinkhaus B, Reinhold T, Willich SN. Efficacy, effectiveness, safety and costs of
acupuncture for chronic pain - results of a large research initiative. Acupuncture in Medicine.
2006; 24 Suppl 1:33-39
500 Witteveen AGH, Sierevelt IN, Blankevoort L, Kerkhoffs GMMJ, van Dijk CN. Intra-articular
sodium hyaluronate injections in the osteoarthritic ankle joint: Effects, safety and dose
dependency. Foot and Ankle Surgery. 2010; 16(4):159-163
501 Woolf AD, Pfleger B. Burden of major musculoskeletal conditions. Bulletin of the World Health
Organisation. 2003; 81(9):646-656
502 World Health Organisation. The burden of musculoskeletal conditions at the start of the new
millenium:report of a WHO scientific group, 2003
503 Wyatt FB, Milam S, Manske RC, Deere R. The effects of aquatic and traditional exercise
programs on persons with knee osteoarthritis. Journal of Strength and Conditioning Research.
2001; 15(3):337-340
504 Yelland MJ, Nikles CJ, McNairn N, Del Mar CB, Schluter PJ, Brown RM. Celecoxib compared with
sustained-release paracetamol for osteoarthritis: a series of n-of-1 trials. Rheumatology. 2007;
46(1):135-140
505 Yen ZS, Lai MS, Wang CT, Chen LS, Chen SC, Chen WJ et al. Cost-effectiveness of treatment
strategies for osteoarthritis of the knee in Taiwan. Journal of Rheumatology. 2004; 31(9):1797-
1803

496
Osteoarthritis
Reference list
506 Yentur EA, Okcu G, Yegul I. The role of trigger point therapy in knee osteoarthritis. Pain Clinic.
2003; 15(4):385-390
507 Yocum D. Safety and efficacy of meloxicam in the treatment of osteoarthritis: A 12-week,
double-blind, multiple-dose, placebo-controlled trial. Archives of Internal Medicine. 2000;
160(19):2947-2954
508 Yurtkuran M, Alp A, Konur S, Ozcakir S, Bingol U. Laser acupuncture in knee osteoarthritis: a
double-blind, randomized controlled study. Photomedicine and Laser Surgery. 2007; 25(1):14-
20
509 Yurtkuran M, Kocagil T. TENS, electroacupuncture and ice massage: comparison of treatment
for osteoarthritis of the knee. American Journal of Acupuncture. 1999; 27(3-4):133-140
510 Zacher J. A comparison of the therapeutic efficacy and tolerability of etoricoxib and diclofenac
Update 2014
in patients with osteoarthritis. Current Medical Research and Opinion. 2003; 19(8):725-736
511 Zegels B, Crozes P, Uebelhart D, Bruyere O, Reginster JY. Equivalence of a single dose (1200mg)
compared to a three-time a day dose (400mg) of chondroitin 4&6 sulfate in patients with knee
osteoarthritis. Results of a randomized double blind placebo controlled study. Osteoarthritis
and Cartilage. 2013; 21(1):22-27
512 Zhang W, Moskowitz RW, Nuki G, Abramson S, Altman RD, Arden N et al. OARSI
recommendations for the management of hip and knee osteoarthritis, Part I: Critical appraisal
of existing treatment guidelines and systematic review of current research evidence.
513 Zhang W, Nuki G, Moskowitz RW, Abramson S, Altman RD, Arden NK et al. OARSI
recommendations for the management of hip and knee osteoarthritis: Part III: changes in
evidence following systematic cumulative update of research published through January 2009.
514 Zhao SZ, McMillen JI, Markenson JA, Dedhiya SD, Zhao WW, Osterhaus JT et al. Evaluation of
the functional status aspects of health-related quality of life of patients with osteoarthritis
treated with celecoxib. Pharmacotherapy. 1999; 19(11):1269-1278

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15 Glossary
Term Description
Abstract Summary of a study, which may be published alone or as an introduction to a
full scientific paper.
Algorithm (in guidelines) A flow chart of the clinical decision pathway described in the guideline, where
decision points are represented with boxes, linked with arrows.
Allocation concealment The process used to prevent advance knowledge of group assignment in a
RCT. The allocation process should be impervious to any influence by the
individual making the allocation, by being administered by someone who is
not responsible for recruiting participants.
Applicability The degree to which the results of an observation, study or review are likely to
hold true in a particular clinical practice setting.
Arm (of a clinical study) Sub-section of individuals within a study who receive one particular
intervention, for example placebo arm
Association Statistical relationship between two or more events, characteristics or other
variables. The relationship may or may not be causal.
Baseline The initial set of measurements at the beginning of a study (after run-in period
where applicable), with which subsequent results are compared.
Before-and-after study A study that investigates the effects of an intervention by measuring particular
characteristics of a population both before and after taking the intervention,
and assessing any change that occurs.
Bias Systematic (as opposed to random) deviation of the results of a study from
the ‘true’ results that is caused by the way the study is designed or conducted.
Blinding Keeping the study participants, caregivers, researchers and outcome assessors
unaware about the interventions to which the participants have been
allocated in a study.
Carer (caregiver) Someone other than a health professional who is involved in caring for a
person with a medical condition.
Case-control study Comparative observational study in which the investigator selects individuals
who have experienced an event (For example, developed a disease) and
others who have not (controls), and then collects data to determine previous
exposure to a possible cause.
Case-series Report of a number of cases of a given disease, usually covering the course of
the disease and the response to treatment. There is no comparison (control)
group of patients.
Clinical efficacy The extent to which an intervention is active when studied under controlled
research conditions.
Clinical effectiveness The extent to which an intervention produces an overall health benefit in
routine clinical practice.
Clinician A healthcare professional providing direct patient care, for example doctor,
nurse or physiotherapist.
Cochrane Review The Cochrane Library consists of a regularly updated collection of evidence-
based medicine databases including the Cochrane Database of Systematic
Reviews (reviews of randomised controlled trials prepared by the Cochrane
Collaboration).
Cohort study A retrospective or prospective follow-up study. Groups of individuals to be
followed up are defined on the basis of presence or absence of exposure to a
suspected risk factor or intervention. A cohort study can be comparative, in
which case two or more groups are selected on the basis of differences in
their exposure to the agent of interest.

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Glossary
Term Description
Comorbidity Co-existence of more than one disease or an additional disease (other than
that being studied or treated) in an individual.
Comparability Similarity of the groups in characteristics likely to affect the study results (such
as health status or age).
Concordance This is a recent term whose meaning has changed. It was initially applied to
the consultation process in which doctor and patient agree therapeutic
decisions that incorporate their respective views, but now includes patient
support in medicine taking as well as prescribing communication.
Concordance reflects social values but does not address medicine-taking and
may not lead to improved adherence.
Confidence interval (CI) A range of values for an unknown population parameter with a stated
‘confidence’ (conventionally 95%) that it contains the true value. The interval
is calculated from sample data, and generally straddles the sample estimate.
The ‘confidence’ value means that if the method used to calculate the interval
is repeated many times, then that proportion of intervals will actually contain
the true value.
Confounding In a study, confounding occurs when the effect of an intervention on an
outcome is distorted as a result of an association between the population or
intervention or outcome and another factor (the ‘confounding variable’) that
can influence the outcome independently of the intervention under study.
Consensus methods Techniques that aim to reach an agreement on a particular issue. Consensus
methods may used when there is a lack of strong evidence on a particular
topic.
Control group A group of patients recruited into a study that receives no treatment, a
treatment of known effect, or a placebo (dummy treatment) - in order to
provide a comparison for a group receiving an experimental treatment, such
as a new drug.
Cost benefit analysis A type of economic evaluation where both costs and benefits of healthcare
treatment are measured in the same monetary units. If benefits exceed costs,
the evaluation would recommend providing the treatment.
Cost-consequences A type of economic evaluation where various health outcomes are reported in
analysis (CCA) addition to cost for each intervention, but there is no overall measure of
health gain.
Cost-effectiveness analysis An economic study design in which consequences of different interventions
(CEA) are measured using a single outcome, usually in ‘natural’ units (For example,
life-years gained, deaths avoided, heart attacks avoided, cases detected).
Alternative interventions are then compared in terms of cost per unit of
effectiveness.
Cost-effectiveness model An explicit mathematical framework, which is used to represent clinical
decision problems and incorporate evidence from a variety of sources in order
to estimate the costs and health outcomes.
Cost-utility analysis (CUA) A form of cost-effectiveness analysis in which the units of effectiveness are
quality-adjusted life-years (QALYs).
Credible Interval The Bayesian equivalent of a confidence interval.
Decision analysis An explicit quantitative approach to decision making under uncertainty, based
on evidence from research. This evidence is translated into probabilities, and
then into diagrams or decision trees which direct the clinician through a
succession of possible scenarios, actions and outcomes.
Discounting Costs and perhaps benefits incurred today have a higher value than costs and
benefits occurring in the future. Discounting health benefits reflects individual
preference for benefits to be experienced in the present rather than the
future. Discounting costs reflects individual preference for costs to be

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Glossary
Term Description
experienced in the future rather than the present.
Dominance An intervention is said to be dominated if there is an alternative intervention
that is both less costly and more effective.
Drop-out A participant who withdraws from a trial before the end.
Economic evaluation Comparative analysis of alternative health strategies (interventions or
programmes) in terms of both their costs and consequences.
Effect (as in effect The observed association between interventions and outcomes or a statistic
measure, treatment effect, to summarise the strength of the observed association.
estimate of effect, effect
size)
Effectiveness See ‘Clinical effectiveness’.
Efficacy See ‘Clinical efficacy’.
Epidemiological study The study of a disease within a population, defining its incidence and
prevalence and examining the roles of external influences (For example,
infection, diet) and interventions.
EQ-5D (EuroQol-5D) A standardise instrument used to measure a health outcome. It provides a
single index value for health status.
Evidence Information on which a decision or guidance is based. Evidence is obtained
from a range of sources including randomised controlled trials, observational
studies, expert opinion (of clinical professionals and/or patients).
Exclusion criteria Explicit standards used to decide which studies should be excluded from
(literature review) consideration as potential sources of evidence.
Exclusion criteria (clinical Criteria that define who is not eligible to participate in a clinical study.
study)
Extended dominance If Option A is both more clinically effective than Option B and has a lower cost
per unit of effect, when both are compared with a do-nothing alternative then
Option A is said to have extended dominance over Option B. Option A is
therefore more efficient and should be preferred, other things remaining
equal.
Extrapolation In data analysis, predicting the value of a parameter outside the range of
observed values.
Follow-up Observation over a period of time of an individual, group or initially defined
population whose appropriate characteristics have been assessed in order to
observe changes in health status or health-related variables.
Generalisability The extent to which the results of a study based on measurement in a
particular patient population and/or a specific context hold true for another
population and/or in a different context. In this instance, this is the degree to
which the guideline recommendation is applicable across both geographical
and contextual settings. For instance, guidelines that suggest substituting one
form of labour for another should acknowledge that these costs might vary
across the country.
Gold standard See GRADE / GRADE profile A system developed by the GRADE Working Group
‘Reference standard’. to address the shortcomings of present grading systems in healthcare. The
GRADE system uses a common, sensible and transparent approach to grading
the quality of evidence. The results of applying the GRADE system to clinical
trial data are displayed in a table known as a GRADE profile.
Harms Adverse effects of an intervention.
Health economics The study of the allocation of scarce resources among alternative healthcare
treatments. Health economists are concerned with both increasing the
average level of health in the population and improving the distribution of
health.

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Glossary
Term Description
Health-related quality of A combination of an individual’s physical, mental and social well-being; not
life (HRQoL) merely the absence of disease.
Heterogeneity Or lack of The term is used in meta-analyses and systematic reviews when the results or
homogeneity. estimates of effects of treatment from separate studies seem to be very
different – in terms of the size of treatment effects or even to the extent that
some indicate beneficial and others suggest adverse treatment effects. Such
results may occur as a result of differences between studies in terms of the
patient populations, outcome measures, definition of variables or duration of
follow-up.
Imprecision Results are imprecise when studies include relatively few patients and few
events and thus have wide confidence intervals around the estimate of effect.
Inclusion criteria (literature Explicit criteria used to decide which studies should be considered as potential
review) sources of evidence.
Incremental analysis The analysis of additional costs and additional clinical outcomes with different
interventions.
Incremental cost The mean cost per patient associated with an intervention minus the mean
cost per patient associated with a comparator intervention.
Incremental cost The difference in the mean costs in the population of interest divided by the
effectiveness ratio (ICER) differences in the mean outcomes in the population of interest for one
treatment compared with another.
Incremental net benefit The value (usually in monetary terms) of an intervention net of its cost
(INB) compared with a comparator intervention. The INB can be calculated for a
given cost-effectiveness (willingness to pay) threshold. If the threshold is
£20,000 per QALY gained then the INB is calculated as: (£20,000 x QALYs
gained) – Incremental cost.
Indirectness The available evidence is different to the review question being addressed, in
terms of PICO (population, intervention, comparison and outcome).
Intention to treat analysis A strategy for analysing data from a randomised controlled trial. All
(ITT) participants are included in the arm to which they were allocated, whether or
not they received (or completed) the intervention given to that arm.
Intention-to-treat analysis prevents bias caused by the loss of participants,
which may disrupt the baseline equivalence established by randomisation and
which may reflect non-adherence to the protocol.
Intervention Healthcare action intended to benefit the patient, for example, drug
treatment, surgical procedure, psychological therapy.
Intraoperative The period of time during a surgical procedure.
Kappa statistic A statistical measure of inter-rater agreement that takes into account the
agreement occurring by chance.
Length of stay The total number of days a participant stays in hospital.
Licence See ‘Product licence’.
Life-years gained Mean average years of life gained per person as a result of the intervention
compared with an alternative intervention.
Likelihood ratio The likelihood ratio combines information about the sensitivity and specificity.
It tells you how much a positive or negative result changes the likelihood that
a patient would have the disease. The likelihood ratio of a positive test result
(LR+) is sensitivity divided by 1- specificity.
Long-term care Residential care in a home that may include skilled nursing care and help with
everyday activities. This includes nursing homes and residential homes.
Markov model A method for estimating long-term costs and effects for recurrent or chronic
conditions, based on health states and the probability of transition between
them within a given time period (cycle).

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Glossary
Term Description
Meta-analysis A statistical technique for combining (pooling) the results of a number of
studies that address the same question and report on the same outcomes to
produce a summary result. The aim is to derive more precise and clear
information from a large data pool. It is generally more reliably likely to
confirm or refute a hypothesis than the individual trials.
Multivariate model A statistical model for analysis of the relationship between two or more
predictor (independent) variables and the outcome (dependent) variable.
Negative predictive value A measure of the usefulness of a screening/diagnostic test. It is the proportion
(NPV) [In of those with a negative test result who do not have the disease, and can be
screening/diagnostic tests:] interpreted as the probability that a negative test result is correct.
Number needed to treat The number of patients that who on average must be treated to prevent a
(NNT) single occurrence of the outcome of interest.
Observational study Retrospective or prospective study in which the investigator observes the
natural course of events with or without control groups; for example, cohort
studies and case–control studies.
Odds ratio A measure of treatment effectiveness. The odds of an event happening in the
treatment group, expressed as a proportion of the odds of it happening in the
control group. The 'odds' is the ratio of events to non-events.
Opportunity cost The loss of other health care programmes displaced by investment in or
introduction of another intervention. This may be best measured by the
health benefits that could have been achieved had the money been spent on
the next best alternative healthcare intervention.
Outcome Measure of the possible results that may stem from exposure to a preventive
or therapeutic intervention. Outcome measures may be intermediate
endpoints or they can be final endpoints. See ‘Intermediate outcome’.
P-value The probability that an observed difference could have occurred by chance,
assuming that there is in fact no underlying difference between the means of
the observations. If the probability is less than 1 in 20, the P value is less than
0.05; a result with a P value of less than 0.05 is conventionally considered to
be ‘statistically significant’.
Perioperative The period from admission through surgery until discharge, encompassing the
pre-operative and post-operative periods.
Placebo An inactive and physically identical medication or procedure used as a
comparator in controlled clinical trials.
Polypharmacy The use or prescription of multiple medications.
Positive predictive value In screening/diagnostic tests: A measure of the usefulness of a
(PPV) screening/diagnostic test. It is the proportion of those with a positive test
result who have the disease, and can be interpreted as the probability that a
positive test result is correct.
Postoperative Pertaining to the period after patients leave the operating theatre, following
surgery.
Post-test probability For diagnostic tests. The proportion of patients with that particular test result
who have the target disorder (post test odds/[1 + post-test odds]).
Power (statistical) The ability to demonstrate an association when one exists. Power is related to
sample size; the larger the sample size, the greater the power and the lower
the risk that a possible association could be missed.
Preoperative The period before surgery commences.
Pre-test probability For diagnostic tests. The proportion of people with the target disorder in the
population at risk at a specific time point or time interval. Prevalence may
depend on how a disorder is diagnosed.

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Glossary
Term Description
Primary care Healthcare delivered to patients outside hospitals. Primary care covers a range
of services provided by general practitioners, nurses, dentists, pharmacists,
opticians and other healthcare professionals.
Primary outcome The outcome of greatest importance, usually the one in a study that the
power calculation is based on.
Product licence An authorisation from the MHRA to market a medicinal product.
Prognosis A probable course or outcome of a disease. Prognostic factors are patient or
disease characteristics that influence the course. Good prognosis is associated
with low rate of undesirable outcomes; poor prognosis is associated with a
high rate of undesirable outcomes.
Prospective study A study in which people are entered into the research and then followed up
over a period of time with future events recorded as they happen. This
contrasts with studies that are retrospective.
Publication bias Also known as reporting bias. A bias caused by only a subset of all the relevant
data being available. The publication of research can depend on the nature
and direction of the study results. Studies in which an intervention is not
found to be effective are sometimes not published. Because of this,
systematic reviews that fail to include unpublished studies may overestimate
the true effect of an intervention. In addition, a published report might
present a biased set of results (e.g. only outcomes or sub-groups where a
statistically significant difference was found.
Quality of life See ‘Health-related quality of life’.
Quality-adjusted life year An index of survival that is adjusted to account for the patient’s quality of life
(QALY) during this time. QALYs have the advantage of incorporating changes in both
quantity (longevity/mortality) and quality (morbidity, psychological,
functional, social and other factors) of life. Used to measure benefits in cost-
utility analysis. The QALYs gained are the mean QALYs associated with one
treatment minus the mean QALYs associated with an alternative treatment.
Quick Reference Guide An abridged version of NICE guidance, which presents the key priorities for
implementation and summarises the recommendations for the core clinical
audience.
Randomisation Allocation of participants in a research study to two or more alternative
groups using a chance procedure, such as computer-generated random
numbers. This approach is used in an attempt to ensure there is an even
distribution of participants with different characteristics between groups and
thus reduce sources of bias.
Randomised controlled A comparative study in which participants are randomly allocated to
trial (RCT) intervention and control groups and followed up to examine differences in
outcomes between the groups.
RCT See ‘Randomised controlled trial’.
Receiver operated A graphical method of assessing the accuracy of a diagnostic test. Sensitivity Is
characteristic (ROC) curve plotted against 1-specificity. A perfect test will have a positive, vertical linear
slope starting at the origin. A good test will be somewhere close to this ideal.
Reference standard The test that is considered to be the best available method to establish the
presence or absence of the outcome – this may not be the one that is
routinely used in practice.
Relative risk (RR) The number of times more likely or less likely an event is to happen in one
group compared with another (calculated as the risk of the event in group
A/the risk of the event in group B).
Reporting bias See publication bias.
Resource implication The likely impact in terms of finance, workforce or other NHS resources.

503
Osteoarthritis
Glossary
Term Description
Retrospective study A retrospective study deals with the present/ past and does not involve
studying future events. This contrasts with studies that are prospective.
Review question In guideline development, this term refers to the questions about treatment
and care that are formulated to guide the development of evidence-based
recommendations.
Secondary outcome An outcome used to evaluate additional effects of the intervention deemed a
priori as being less important than the primary outcomes.
Selection bias A systematic bias in selecting participants for study groups, so that the groups
have differences in prognosis and/or therapeutic sensitivities at baseline.
Randomisation (with concealed allocation) of patients protects against this
bias.
Sensitivity Sensitivity or recall rate is the proportion of true positives which are correctly
identified as such. For example in diagnostic testing it is the proportion of true
cases that the test detects.
See the related term ‘Specificity’
Sensitivity analysis A means of representing uncertainty in the results of economic evaluations.
Uncertainty may arise from missing data, imprecise estimates or
methodological controversy. Sensitivity analysis also allows for exploring the
generalisability of results to other settings. The analysis is repeated using
different assumptions to examine the effect on the results.
One-way simple sensitivity analysis (univariate analysis): each parameter is
varied individually in order to isolate the consequences of each parameter on
the results of the study.
Multi-way simple sensitivity analysis (scenario analysis): two or more
parameters are varied at the same time and the overall effect on the results is
evaluated.
Threshold sensitivity analysis: the critical value of parameters above or below
which the conclusions of the study will change are identified.
Probabilistic sensitivity analysis: probability distributions are assigned to the
uncertain parameters and are incorporated into evaluation models based on
decision analytical techniques (For example, Monte Carlo simulation).
Significance (statistical) A result is deemed statistically significant if the probability of the result
occurring by chance is less than 1 in 20 (p <0.05).
Specificity The proportion of true negatives that a correctly identified as such. For
example in diagnostic testing the specificity is the proportion of non-cases
incorrectly diagnosed as cases.
See related term ‘Sensitivity’.
In terms of literature searching a highly specific search is generally narrow and
aimed at picking up the key papers in a field and avoiding a wide range of
papers.
Stakeholder Those with an interest in the use of the guideline. Stakeholders include
manufacturers, sponsors, healthcare professionals, and patient and carer
groups.
Systematic review Research that summarises the evidence on a clearly formulated question
according to a pre-defined protocol using systematic and explicit methods to
identify, select and appraise relevant studies, and to extract, collate and
report their findings. It may or may not use statistical meta-analysis.
Time horizon The time span over which costs and health outcomes are considered in a
decision analysis or economic evaluation.
Treatment allocation Assigning a participant to a particular arm of the trial.
Univariate Analysis which separately explores each variable in a data set.

504
Osteoarthritis
Glossary
Update 2014
Term Description
Utility A measure of the strength of an individual’s preference for a specific health
state in relation to alternative health states. The utility scale assigns numerical
values on a scale from 0 (death) to 1 (optimal or ‘perfect’ health). Health
states can be considered worse than death and thus have a negative value.

505

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National Clinical Guideline Centre

Clinical guideline CG177

Commissioned by the National Institute for Health and Care

National Clinical Guideline Centre, 2014

National Clinical Guideline Centre, 2014

4.1 Algorithms ........................................................................................................................... 38

National Clinical Guideline Centre, 2014

7.3.1 Clinical introduction ............................................................................................... 98

National Clinical Guideline Centre, 2014

8.3.3 Evidence statements: ultrasound ........................................................................ 151

National Clinical Guideline Centre, 2014

inhibitors .............................................................................................................. 259

National Clinical Guideline Centre, 2014

10.2 Intra-articular injections of hyaluronic acid/ hyaluronans in the management of OA in

National Clinical Guideline Centre, 2014

15 Glossary ............................................................................................................................ 498

National Clinical Guideline Centre, 2014

Guideline development group members

Professor Philip Conaghan Chair of the GDG

National Clinical Guideline Centre, 2014

National Clinical Guideline Centre, 2014

• Dr Phil Alderson, National Institute for Health and Care Excellence

• Mr Garry Barton, School of Economics, University of Nottingham

• Professor Chris Hawkey, Institute of Clinical Research, University of Nottingham

• Dr Jayne Spink, National Institute for Health and Care Excellence

• Dr Rafe Suvarna, Medicines and Healthcare Regulatory Agency

• Professor Richard Thomson, Professor of Epidemiology and Public Health, University of

• Dr Weiya Zhang, Associate Professor, Centre for Population Sciences, University of

National Clinical Guideline Centre, 2014

Osteoarthritis is characterised pathologically by localised loss of cartilage, remodelling of adjacent

National Clinical Guideline Centre, 2014

1.2 Risk factors for osteoarthritis

1.3 The epidemiology of osteoarthritis pain and structural pathology

National Clinical Guideline Centre, 2014

The relationship between symptomatic and radiographic osteoarthritis

Table 1: Prevalence of radiographic and symptomatic osteoarthritis in older adults

1.4 Prognosis and Outcome

National Clinical Guideline Centre, 2014

1.5 The impact on the individual

National Clinical Guideline Centre, 2014

1.6 The impact on society

Osteoarthritis has considerable impact on health services:

1.7 Features of the evidence base for osteoarthritis

base is particularly lacking.

National Clinical Guideline Centre, 2014

National Clinical Guideline Centre, 2014

2 Development of the guideline

NICE clinical guidelines can:

We produce our guidelines using the following steps:

The NCGC and NICE produce a number of versions of this guideline:

2.2 Who developed this guideline?

National Clinical Guideline Centre, 2014

2.3 What this guideline covers

2.5 Relationships between the guideline and other NICE guidance

National Clinical Guideline Centre, 2014

National Clinical Guideline Centre, 2014

3.1 Developing the review questions and outcomes

-Crystal arthritis (gout or

National Clinical Guideline Centre, 2014

Chapter Review questions Outcomes

National Clinical Guideline Centre, 2014

Chapter Review questions Outcomes

3.2 Searching for evidence

National Clinical Guideline Centre, 2014